N-heteroaryl-N&#39;-phenylurea derivatives, their production and use

ABSTRACT

An N-heteroaryl-N&#39;-phenylurea derivative represented by the general formula (I): ##STR1## wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are as defined in the description of the specification which is useful as a prophylactic and therapeutic agent for hypercholesterolemia, atherosclerosis and diseases caused by them.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to N-heteroaryl-N'-phenylurea derivativesor pharmacologically acceptable salts thereof, which have inhibitoryeffect on acyl-CoA:cholesterol O-acyltransferase (ACAT).

The compounds of the present invention have the effect of reducing serumcholesterol by inhibiting the absorption of cholesterol from intestinaltract and suppress the accumulation of cholesterol esters in thearterial wall. Therefore, they are useful as a prophylactic andtherapeutic agent for hypercholesterolemia, atherosclerosis and variousdiseases caused by them (for example, ischemic heart diseases such asmyocardial infarction, and cerebrovascular diseases such as cerebralinfarction and cerebral apoplexy).

2. Related Art

As to N-heteroaryl-N'-phenylurea derivatives, there are the followingdisclosures.

Japanese Patent Unexamined Publication No. 3-7259 discloses thatN-quinoline-N'-phenylurea derivatives represented by the formula (A):##STR2## (wherein the ring A, ring B and ring C may have a substituent,and each of m and n is zero or an integer of 1) have ACAT-inhibitoryactivity. Japanese Patent Unexamined Publication No. 3-223254 disclosesthat N-quinoline-N'-phenylurea derivatives represented by the formula(B): ##STR3## (wherein the ring A', ring B and ring C' may have asubstituent, n is zero or an integer of 1, and X' is ##STR4## haveACAT-inhibitory activity.

J. Ind. Chem. Soc., 1978, 55(9), 910-913 discloses that compoundshaving, like the compounds of the present invention, a benzofuranskeleton which are represented by the formula (C): ##STR5## (wherein Reis a hydrogen atom or a methyl group) have antimicrobial activity,antibacterial activity, antiparasitic activity and anti-amoeba activity.

Farmaco, Ed. Sci. 1979, 34(6), 507-517 describes compounds having anindole skeleton which are represented by the formula (D): ##STR6## butit does not describes them as having ACAT-inhibitory activity.

OBJECT AND SUMMARY OF THE INVENTION

The present inventors investigated N-heteroaryl derivatives andconsequently found that a compound represented by the general formula(I): ##STR7## wherein R¹ and R², which may be the same or different, arehydrogen atoms; halogen atoms; unsubstituted C₁ -C₁₀ alkyl groups;substituted C₁ -C₆ alkyl groups having a C₂ -C₈ -dialkylamino group asthe substituent; substituted lower alkyl groups having as thesubstituent a saturated cyclic amino group which may have a heteroatomin the ring; C₁ -C₆ alkoxy groups; or nitro groups, R¹ and R² being ableto be taken together to represent a C₃ -C₆ alkylene group, R³ and R⁴,which may be the same or different, are hydrogen atoms, halogen atoms,C₁ -C₆ alkyl groups, C₁ -C₆ haloalkyl groups, C₁ -C₆ alkoxy groups or C₁-C₆ alkylthio groups, R⁵, R⁶ and R⁷, which may be the same or different,are hydrogen atoms, halogen atoms, C₁ -C₈ alkyl groups, C₁ -C₆ haloalkylgroups, C₃ -C₇ alkenyl groups, C₁ -C₆ alkoxy groups, C₁ -C₆ alkylthiogroups or C₂ -C₈ -dialkylamino groups, and X is --O--, --S-- or --NR--(wherein R is a C₁ -C₆ alkyl group, a phenylsulfonyl group or atoluenesulfonyl group) or a pharmacologically acceptable salt thereof isa novel compound not known in any literature and has an excellentACAT-inhibiting activity, whereby the present invention has beenaccomplished.

An object of the present invention is to provide novelN-heteroaryl-N'-phenylurea derivatives having an excellent ACATinhibitory activity.

An another object of the present invention is to provide apharmaceutical composition useful as a prophylactic and therapeuticagent for hypercholesterolemia, arteriosclerosis and diseases caused bythem.

An further another object of the present invention is to provide amethod of preparing N-heteroaryl-N'-phenylurea derivatives.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the above general formula (I), the halogen atoms include fluorineatom, chlorine atom, bromine atom and iodine atom. The lower alkylgroups include linear or branched alkyl groups having 1 to 6 carbonatoms, such as methyl, ethyl, n-propyl, isoproyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylbutyl,2-methylbutyl, 1,2-dimethylpropyl, n-hexyl, isohexyl, 1-methylpentyl,2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,2,2-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and the like. The lowerhaloalkyl groups include trichloromethyl group, trifluoromethyl group,1,1,1-trifluoroethyl group, etc. The lower alkoxy groups include methoxygroup, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group,isobutoxy group, sec-butoxy group, tert-butoxy group, etc. The loweralkylthio groups include methylthio group, ethylthio group, n-propylthiogroup, isopropylthio group, n-butylthio group, isobutylthio group,sec-butylthio group, tert-butylthio group, etc.

Preferable N-heteroaryl-N'-phenylurea derivatives are those whose R¹ isa halogen atom or a C₁ -C₁₀ alkyl group, R² is a hydrogen atom or a C₁-C₆ alkyl group, R¹ and R² being able to be taken together to representa C₃ -C₆ alkylene group, R³ is a halogen atom, a C₁ -C₄ alkyl group, aC₁ -C₄ alkylthio group or trifluoromethyl group, R⁴ is a hydrogen atomor a halogen atom, R⁵ and R⁶ which may be the same or different, arehalogen atoms or C₁ -C₄ alkyl groups, and R⁷ is a hydrogen atom or ahalogen atom.

More preferable N-heteroaryl-N'-phenylurea derivatives are those whoseR¹ is a chlorine atom or a C₁ -C₈ alkyl group, R² is a halogen atom or aC₁ -C₃ alkyl group, R¹ and R² being able to be taken together torepresent a C₃ -C₄ alkylene group, R³ is a halogen atom, a C₁ -C₄ alkylgroup or a C₁ -C₄ alkylthio group, R⁴ is a hydrogen atom, R⁵ and R⁶which may be the same, are halogen atoms or C₁ -C₄ alkyl groups, and R⁷is a hydrogen atom.

Of the compound of the present invention, those which are particularlyuseful as an ACAT inhibitor will be shown bellow:

N-[5-chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2,6-diethylphenyl)urea,

N-[5-chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea,

N-[3-(2-chlorophenyl)-5-hexylbenzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea,

N-[3-(2-chlorophenyl)-5,7-dimethylbenzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea,

N-[5-chloro-3-(2-methylphenyl)benzofuran-2-yl]-N'-(2,6-diethylphenyl)urea,

N-(3-(2-chlorophenyl)-5-isopropyl-1-benzothiophen-2-yl]-N'-(2,6-diethylphenyl)urea,

N-[3-(2-chlorophenyl)-5-isoproyl-1-benzothiophen-2-yl]-N"-2,6-diisopropylphenyl)urea,

N-[3-(2-chlorophenyl)-5,6-dimethyl-1-benzothiophen-2-yl]-N'-(2,6-diethylphenyl)urea,

N-2,6-diethylphenyl)-N'-[3-(2-methylphenyl)-6,7-dihydro-5H-cyclopenta[f][1]-benzothiophen-2-yl]urea,

N-3-(2-chlorophenyl)-5-fluorobenzofuran-2-yl]-N'-(2,6-diethylphenyl)urea,

N-[5-chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2,6-dimethylamino-6-methylphenyl)urea,

N-[3-(2-chlorophenyl)-5-ethylbenzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea,

N-[3-(2-chlorophenyl)-5,6-dimethylbenzofuran-2-yl]-N'-(2,6-diethylphenyl)urea,

N-[5-chloro-3-(2-methylthiophenyl)benzofuran-2-yl]-N'-(2,6-diethylphenyl)urea,

N-[5-chloro-3-(2-chlorophenyl)-1-benzothiophen-2-yl]-N'-(2,6-diethylphenyl)urea,

N-[3-(2-chlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]-N'-(2,4-difluorophenyl)urea,

N-[3-(2-chlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]-N'-(2,4,6-trifluorophenyl)urea,

N-[3-(2-chlorophenyl)-5,6,7,8-tetrahydronaphtho[2,3-b]thiophen-2-yl]-N'-(2-isopropyl-6-methylphenyl)urea,and

N-(2-isopropyl-6-methylphenyl)-N'-[3-(2-methylphenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]urea.

The compound of the general formula (I) can be synthesized by a processrepresented by the following formulas: ##STR8## wherein R¹, R², R³, R⁴,R⁵, R⁶, R⁷ and X are as defined above.

In detail, the compound of the general formula (I) can be produced byreacting a compound of the general formula (II) with diphenylphosphorylazide in the presence of an organic amine such as triethylamine in aninert solvent such as benzene, toluene, xylene or dioxane in atemperature range of room temperature to about 150° C. to obtain anisocyanate (III), and then reacting the isocyanate with a compound ofthe general formula (IV) in a temperature range of room temperature toabout 150° C. after or without isolating the isocyanate. Since thereactions are equimolar reactions, it is sufficient that the reactantsfor carrying out each reaction are used in equimolar amounts, thougheither of them may be used in excess.

The compounds of the general formula (II) used in the reaction can besynthesized by any of the following processes.

Process A (in the case where X═O)

The compound of the general formula (II) can be synthesized from acompound of the formula (V) by the process described in J. Ind. Chem.Soc. 33, 339 (1956) and Brit. 705,950 or a process based thereon.##STR9## wherein R¹, R², R³ and R⁴ are as defined above, R' is a loweralkyl group, Y is a halogen atom such as a chlorine atom or bromineatom, and Z is a diazo group.

In detail, a phenol (V) is benzoylated into a compound (VII) by aconventional method, and the compound (VII) is heated in the presence ofa Lewis acid (e.g. aluminum chloride, aluminum bromide or titaniumtetrabromide) to obtain a hydroxybenzophenone (VIII). This reaction canbe carried out in an inert solvent such as carbon disulfide ornitrobenzene or without a solvent in a temperature range of roomtemperature to about 180° C. Then, the compound (VIII) is reacted with acompound (IX) in the presence of an inorganic base (e.g. potassiumcarbonate, sodium carbonate or lithium carbonate) in a solvent (e.g.dimethylformamide, dimethyl sulfoxide, acetonitrile or acetone) in atemperature range of room temperature to about 100° C. to obtain acompound (X). Next, the compound (X) is subjected to ring-closingreaction with a metal alkoxide (e.g. sodium methoxide, sodium ethoxide,sodium isopropoxide or potassium t-butoxide) in a solvent (e.g.methanol, ethanol, isopropanol, t-butanol, tetrahydrofuran or dioxane)in a temperature range of room temperature to about 80° C. to obtain abenzofuran (XI). Subsequently, the compound (XI) is hydrolyzed with anaqueous alkali metal hydroxide solution such as sodium hydroxide orpotassium hydroxide, trifluoroacetic acid, or a mineral acid (e.g.hydrochloric acid, sulfuricacid or hydrobromic acid) in a solvent (e.g.methanol, ethanol, isopropanol or dioxane) in a temperature range ofroom temperature to about 120° C. to obtain a compound (IIa).

The compound of the formula (XI) can be obtained also by reacting anα-diazobenzoylacetic acid ester (XII) with a phenol (V) in the presenceof a rhodium(II) carboxylate catalyst such as rhodium(II) acetate in asolvent such as carbon tetrachloride or acetonitrile in a temperaturerange of room temperature to about 50° C. to obtain a compound (XIII),and then reacting the compound (XIII) with sulfuric acid in atemperature range of approximately 0°-10° C.

Process B (in the case where X═S)

The compound of the general formula (II) can be synthesized from acompound of the formula (XIV) by the process described in J. Org. Chem.23, 206 (1958) or a process based thereon. wherein R¹, R², R³ and R⁴ areas defined above.

In further detail, a compound (XIV) is reacted with a benzoyl chloridein the presence of a Lewis acid (e.g. aluminum chloride or tintetrachloride) to obtain a compound (XV). Usually, this reaction can becarried out by the use of or without a solvent (e.g. carbon disulfide ornitrobenzene) in a temperature range of room temperature to about 100°C. Then, the compound (XV) is reacted with chloroacetic acid in atemperature range of approximately 80°-130° C. to obtain benzothiopheneor a derivative thereof (IIb).

Process C (in the case where X═ ##STR10##

The compound of the general formula (II) can be synthesized from acompound of the formula (XVI) by the process described in J. Org. Chem.37, 3624 (1972) or a process based thereon. ##STR11## wherein R¹, R²,R³, R⁴, R' and Y are as defined above, and R" is a phenyl group or atoluyl group.

In further detail, a 2-aminobenzophenone (XVI) is converted into acompound (XVIII) by a conventional method, and this compound is reactedwith a compound (IX) in the presence of a metal hydride (e.g. sodiumhydride or potassium hydride) in a solvent (e.g. dimethylformamide ordimethyl sulfoxide) in a temperature range of approximately 0°-50° C. toobtain a compound (XIX). Then, the compound (XIX) is reacted with ametal alkoxide (e.g. sodium methoxide, sodium ethoxide, sodiumisopropoxide or potassium t-butoxide) in an ordinary solvent (e.g.methanol, ethanol, isopropanol or t-butanol) in a temperature range ofroom temperature to about 80° C. to obtain a compound (XX). Next, thecompound (XX) is reacted with a halogenating agent (e.g. thionylchloride or phosphorus oxychloride) in the presence of an organic aminesuch as pyridine or triethylamine in an inert solvent (e.g. benzene,toluene or xylene) in a temperature range of approximately 0°-50° C. toobtain a compound (XXI). Subsequently, the compound (XXI) is hydrolyzedwith an acid or an alkali to obtain a compound (IIc).

Process D (in the case where X═--NR--)

The compound of the general formula (II) can be synthesized by theprocess described in J. Org. Chem. 37, 3624 (1972) or a process basedthereon, by using a compound of the formula (XXII) synthesized accordingto Japanese Patent Unexamined Publication No. 3-130252, as a startingmaterial. ##STR12## wherein R¹, R², R³, R⁴, R' and Y are as definedabove, and R is a lower alkyl group.

In further detail, a compound (XXIV) is obtained from the compound(XXII) through a compound (XXIII) by the same process as the productionprocess of the compound (XXI). The obtained compound (XXIV) ishydrolyzed with an aqueous alkali metal hydroxide solution such assodium hydroxide or potassium hydroxide in a solvent such as methanol,ethanol, isopropanol or t-butanol in a temperature range of roomtemperature to about 80° C. to obtain a carboxylic acid (XXV). Then, thecarboxylic acid (XXV) is reacted with an alkylating agent (e.g. an alkyliodide, alkyl bromide or dialkyl sulfate) in the presence of a metalhydride (e.g. sodium hydride or potassium hydride) in a solvent (e.g.dimethylformamide or dimethyl sulfoxide) in a temperature range ofapproximately 0°-50° C. to obtain a compound (XXVI). Subsequently, thecompound (XXVI) is hydrolyzed under alkaline conditions to obtain acompound (IId).

Specific examples of compounds of the general formula (I) obtained bythe above production processes are given in Table 1.

In the Table, the following abbreviation are used to stand for thesubstituent groups as specified below:

Me; methyl,

Et; ethyl,

iPr; isopropyl,

t-Bu; tert-butyl,

nHex; n-hexane, and

Tos; toluenesulfonyl.

                                      TABLE 1                                     __________________________________________________________________________     ##STR13##                                                                    Compound                                                                      No.   X   R.sup.1   R.sup.2                                                                           R.sup.3                                                                           R.sup.4                                                                           R.sup.5                                                                            R.sup.6                                                                           R.sup.7                              __________________________________________________________________________    1     O   5-F       H   2-Cl                                                                              H   2-Et 6-Et                                                                              H                                    2     O   5-F       H   2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    3     O   5-F       H   2-Cl                                                                              H   2-F  4-F H                                    4     O   5-Cl      H   2-Cl                                                                              H   H    H   H                                    5     O   5-Cl      H   2-Cl                                                                              H   2-Me H   H                                    6     O   5-Cl      H   2-Cl                                                                              H                                                                                  ##STR14##                                                                         H   H                                    7     O   5-Cl      H   2-Cl                                                                              H   2-CF.sub.3                                                                         H   H                                    8     O   5-Cl      H   2-Cl                                                                              H   2-OMe                                                                              H   H                                    9     O   5-Cl      H   2-Cl                                                                              H   2-SMe                                                                              H   H                                    10    O   5-Cl      H   2-Cl                                                                              H   2-OMe                                                                              4-OMe                                                                             6-OMe                                11    O   5-Cl      H   2-Cl                                                                              H   2-Me 6-Me                                                                              H                                    12    O   5-Cl      H   2-Cl                                                                              H   2-Et 6-Et                                                                              H                                    13    O   5-Cl      H   2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    14    O   5-Cl      H   2-Cl                                                                              H   2-Et 6-Me                                                                              H                                    15    O   5-Cl      H   2-Cl                                                                              H   2-iPr                                                                              6-Me                                                                              H                                    16    O   5-Cl      H   2-Cl                                                                              H   2-t-Bu                                                                             6-Me                                                                              H                                    17    O   5-Cl      H   2-Cl                                                                              H   2-F  4-F H                                    18    O   5-Cl      H   2-Cl                                                                              H   2-Br 6-Br                                                                              H                                    19    O   5-Cl      H   2-Cl                                                                              H   2-NMe.sub.2                                                                        6-Me                                                                              H                                    20    O   5-Me      H   H   H   2-iPr                                                                              6-iPr                                                                             H                                    21    O   5-Me      H   2-Cl                                                                              H   2-Et 6-Et                                                                              H                                    22    O   5-Me      H   2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    23    O   5-Me      H   2-Cl                                                                              H   2-F  4-F H                                    24    O   5-Et      H   2-Cl                                                                              H   2-Et 6-Et                                                                              H                                    25    O   5-Et      H   2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    26    O   5-Et      H   2-Cl                                                                              H   2-F  4-F H                                    27    O   5-nHex    H   2-Cl                                                                              H   2-iPr                                                                              6-Et                                                                              H                                    28    O   5-nHex    H   2-Cl                                                                              H   2-F  4-F H                                    29    O   5-OMe     H   2-Cl                                                                              H   2-Et 6-Et                                                                              H                                    30    O   5-OMe     H   2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    31    O   5-OMe     H   2-Cl                                                                              H   2-F  4-F H                                    32    O   5-CH.sub.2 NMe.sub.2                                                                    H   2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    33    O                                                                                  ##STR15##                                                                              H   2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    34    O                                                                                  ##STR16##                                                                              H   2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    35    O                                                                                  ##STR17##                                                                              H   2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    36    O   5-Me      6-Me                                                                              2-Cl                                                                              H   2-Me 6-Me                                                                              H                                    37    O   5-Me      6-Me                                                                              2-Cl                                                                              H   2-Et 6-Et                                                                              H                                    35    O   5-Me      6-Me                                                                              2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    39    O   5-Me      6-Me                                                                              2-Cl                                                                              H   2-iPr                                                                              6-Me                                                                              H                                    40    O   5-Me      6-Me                                                                              2-Cl                                                                              H   2-F  4-F H                                    41    O   5-Me      7-Me                                                                              2-Cl                                                                              H   2-Me 6-Me                                                                              H                                    42    O   5-Me      7-Me                                                                              2-Cl                                                                              H   2-Et 6-Et                                                                              H                                    43    O   5-Me      7-Me                                                                              2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    44    O   5-Me      7-Me                                                                              2-Cl                                                                              H   2-iPr                                                                              6-Me                                                                              H                                    45    O   5-Me      7-Me                                                                              2-Cl                                                                              H   2-Me 4-Me                                                                              6-Me                                 46    O   5-Me      7-Me                                                                              2-Cl                                                                              H   2-F  4-F H                                    47    O   5-Me      7-Me                                                                              2-Cl                                                                              H   2-F  6-F H                                    48    O   5-Me      7-Me                                                                              2-Cl                                                                              H   2-F  4-F 6F                                   49    O   5-Me      7-Me                                                                              2-Cl                                                                              H   2-Cl 6-Cl                                                                              H                                    50    O   5-Me      7-Me                                                                              2-Cl                                                                              H   2-Cl H   H                                    51    O   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              H   2-Me 6-Me                                                                              H                                    52    O   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              H   2-Et 6-Et                                                                              H                                    53    O   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    54    O   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              H   2-Me 4-Me                                                                              6-Me                                 55    O   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              H   2-F  4-F H                                    56    O   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              H   2-F  4-F 6F                                   57    O   5-Cl      H   2-F H   2-Et 6-Et                                                                              H                                    58    O   5-Cl      H   2-F H   2-iPr                                                                              6-iPr                                                                             H                                    59    O   5-Cl      H   2-F H   2-F  4-F H                                    60    O   5-Cl      H   2-Me                                                                              H   2-Et 6-Et                                                                              H                                    61    O   5-Cl      H   2-Me                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    62    O   5-Cl      H   2-SMe                                                                             H   2-Et 6-Et                                                                              H                                    63    O   5-Cl      H   2-SMe                                                                             H   2-iPr                                                                              6-iPr                                                                             H                                    64    S   5-Cl      H   2-Cl                                                                              H   2-Me 6-Me                                                                              H                                    65    S   5-Cl      H   2-Cl                                                                              H   2-Et 6-Et                                                                              H                                    66    S   5-Cl      H   2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    67    S   5-Cl      H   2-Cl                                                                              H   2-iPr                                                                              6-Me                                                                              H                                    68    S   5-Cl      H   2-Cl                                                                              H   2-F  4-F H                                    69    S   5-Cl      H   2-Cl                                                                              H   2-F  6-F H                                    70    S   5-Cl      H   2-Cl                                                                              H   2-F  6-F 6-F                                  71    S   5-Cl      H   2-Cl                                                                              H   2-Cl 6-Cl                                                                              H                                    72    S   5-Me      H   2-Cl                                                                              H   2-Et 6-Et                                                                              H                                    73    S   5-Me      H   2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    74    S   5-Me      H   2-Cl                                                                              H   2-iPr                                                                              6-Me                                                                              H                                    75    S   5-Me      H   2-Cl                                                                              H   2-F  4-F H                                    76    S   5-iPr     H   2-Cl                                                                              H   2-Et 6-Et                                                                              H                                    77    S   5-iPr     H   2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    78    S   5-iPr     H   2-Cl                                                                              H   2-F  4-F H                                    79    S   5-Me      6-Me                                                                              2-Cl                                                                              H   2-Me 4-Me                                                                              H                                    80    S   5-Me      6-Me                                                                              2-Cl                                                                              H   2-Et 6-Et                                                                              H                                    81    S   5-Me      6-Me                                                                              2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    82    S   5-Me      6-Me                                                                              2-Cl                                                                              H;  2-iPr                                                                              6-Me                                                                              H                                    83    S   5-Me      6-Me                                                                              2-Cl                                                                              H   2-NMe                                                                              6-Me                                                                              H                                    84    S   5-Me      6-Me                                                                              2-Cl                                                                              H   2-F  4-F H                                    85    S   5-Me      6-Me                                                                              2-Cl                                                                              H   2-F  4-Me                                                                              H                                    86    S   5-Me      6-Me                                                                              2-Cl                                                                              H   2-OMe                                                                              4-OMe                                                                             6-OMe                                87    S   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              H   2-Me 6-Me                                                                              H                                    88    S   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              H   2-Et 6-Et                                                                              H                                    89    S   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    90    S   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              H   2-iPr                                                                              6-Me                                                                              H                                    91    S   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              H   2-NMe                                                                              6-Me                                                                              H                                    92    S   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              H   2-F  4-F H                                    93    s   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              H   2-F  6-F H                                    94    S   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              H   2-F  4-F 6-F                                  95    S   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              H   2-Cl 6-Cl                                                                              H                                    96    S   5,6-(CH.sub.2).sub.4 --                                                                     2-Cl                                                                              H   2-Et 6-Et                                                                              H                                    97    S   5,6-(CH.sub.2).sub.4 --                                                                     2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    98    S   5,6-(CH.sub.2).sub.4 --                                                                     2-Cl                                                                              H   2-iPr                                                                              6-Me                                                                              H                                    99    S   5,6-(CH.sub.2).sub.4 --                                                                     2-Cl                                                                              H   2-F  4-F H                                    100   S   5-NO.sub.2                                                                              H   2-Cl                                                                              4-Cl                                                                              2-iPr                                                                              6-iPr                                                                             H                                    101   S   5-NO.sub.2                                                                              H   2-Cl                                                                              4-Cl                                                                              2-F  4-F H                                    102   S   5-OMe     6-Me                                                                              2-Cl                                                                              H   2-Et 6-Et                                                                              H                                    103   S   5-OMe     6-Me                                                                              2-Cl                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    104   S   5-OMe     6-Me                                                                              2-Cl                                                                              H   2-iPr                                                                              6-Me                                                                              H                                    105   S   5-OMe     6-Me                                                                              2-Cl                                                                              H   2-F  4-F H                                    106   S   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              4-Cl                                                                              2-iPr                                                                              6-iPr                                                                             H                                    107   S   5,6-(CH.sub.2).sub.3 --                                                                     2-Cl                                                                              4-Cl                                                                              2-F  4-F H                                    108   S   5,6-(CH.sub.2).sub.3 --                                                                     2-F H   2-Et 6-Et                                                                              H                                    109   S   5,6-(CH.sub.2).sub.3 --                                                                     2-Me                                                                              H   2-Et 6-Et                                                                              H                                    110   S   5,6-(CH.sub.2).sub.3 --                                                                     2-Me                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    111   S   5,6-(CH.sub.2).sub.3 --                                                                     2-Me                                                                              H   2-iPr                                                                              6-Me                                                                              H                                    112   S   5,6-(CH.sub.2).sub.3 --                                                                     2-Me                                                                              H   2-F  4-F H                                    113   S   5,6-(CH.sub.2).sub.3 --                                                                     2-CF.sub.3                                                                        H   2-Et 6-Et                                                                              H                                    114   S   5,6-(CH.sub.2).sub.3 --                                                                     2-CF.sub.3                                                                        H   2-iPr                                                                              6-iPr                                                                             H                                    115   S   5,6-(CH.sub.2).sub.3 --                                                                     2-CF.sub.3                                                                        H   2-F  4-F H                                    116   S   5,6-(CH.sub.2).sub.3 --                                                                     2-OMe                                                                             H   2-Et 6-Et                                                                              H                                    117   S   5,6-(CH.sub.2).sub.4 --                                                                     2-Me                                                                              H   2-Et 6-Et                                                                              H                                    118   S   5,6-(CH.sub.2).sub.3 --                                                                     2-Me                                                                              H   2-iPr                                                                              6-iPr                                                                             H                                    119   S   5,6-(CH.sub.2).sub.3 --                                                                     2-Me                                                                              H   2-F  4-F H                                    120   N-ToS                                                                             H         H   H   H   2-F  4-F H                                    121   N-ToS                                                                             5-Me      7-Me                                                                              2-Cl                                                                              H   2-iPr                                                                              6-Me                                                                              H                                    122   N-ToS                                                                             5-Me      7-Me                                                                              2-Cl                                                                              H   2-F  4-F H                                    123   NMe 5-Me      7-Me                                                                              2-Cl                                                                              H   2-iPr                                                                              6-Me                                                                              H                                    124   NMe 5-Me      7-Me                                                                              2-Cl                                                                              H   2-F  4-F H                                    125   NMe 5-Me      7-Me                                                                              2-Cl                                                                              H   4-NMe.sub.2                                                                        H   H                                    __________________________________________________________________________

Examples, reference examples, formulation examples and test examples ofthe present invention are described below but should not be construed aslimiting the scope of the invention.

EXAMPLE 1

N-[3-(2-(Chlorophenyl)-5-fluorobenzofuran-2-yl]-N'-(2,6-diethylphenyl)urea(compound 1)

To a stirred mixture of 436 mg of3-(2-chlorophenyl)-5-fluorobenzofuran-2-carboxylic acid and 0.36 cc ofdiphenylphosphoryl azide in 4 cc of benzene was added dropwise 0.23 ccof triethylamine at room temperature. The resulting mixture was stirredat room temperature for 30 minutes and then heated under reflux for 10minutes. After cooling, 0.28 cc of 2,6-diethylaniline was added,followed by refluxing for 3 hours. After cooling, water was added to thereaction mixture and extracted with chloroform. The extract was driedover magnesium sulfate, and distilled to remove the solvent. The crudeproduct thus obtained was purified by a silica gel column chromatography(eluent: chloroform) to obtain 400 mg of compound 1.

Yield 61.0%, m.p. 218°-219° C.

NMR (δ, ppm; DMSO-d₆)

1.08 (t, 6H), 2.47 (q, 4H), 7.05-7.15 (m, 5H),

7.44-7.64 (m, 5H), 7.89 (s, 1H), 9.15 (s, 1H).

The compounds described in Examples 2 to 20 were obtained in the samemanner as in Example 1.

Example 2

N-[3-(2-Chlorophenyl)-5-fluorobenzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 2)

Yield 40.8%, m.p. 230°-231° C.

NMR (δ, ppm; DMSO-d₆) 1.10 (d, 12H), 3.06 (m, 2H), 7.10-7.22 (m, 5H),7.44-7.63 (m, 5H), 7.88 (s, 1H), 9.12 1H).

Example 3

N-[3-(2-(Chlorophenyl)-5-fluorobenzofuran-2-yl]-N'-(2,4-difluorophenyl)urea(compound 3)

Yield 52.9%, m.p. 196°-198° C.

NMR (δ, ppm; DMSO-d₆) 7.03-7.16 (m, 5H), 7.46-7.65 (m, 5H), 8.74 (s,1H), 9.31 (d, 1H).

Example 4

N-[5-Chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-phenylurea (compound4)

Yield 54.6%, m.p. 193°-195° C.

NMR (δ, ppm; DMSO-d₆) 6.99 (t, 1H), 7.23-7.67 (m, 11H), 8.90 (s, 1H),9.07 (s, 1H).

Example 5

N-[5-Chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2-methylphenyl)urea(compound 5)

Yield 57.6%, m.p. 234°-235° C.

NMR (6, ppm; DMSO-d₆) 2.17 (s, 3H), 6.98 (t, 1H), 7.15 (q, 2H), 7.27 (d,1H), 7.33 (dd, 1H), 7.47-7.66 (m, 4H), 8.16 (s, 1H), 9.36 (s, 1H).

Example 6

N-[5-Chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2-isopropenylphenyl)urea(compound 6)

Yield 25.8%, m.p. 191°-194° C.

NMR (δ, ppm; DMSO-d₆) 1.99 (s, 3H), 4.95 (s, 1H), 5.28 (d, 1H),7.04-7.36 (m, 5H), 7.46-7.72 (m, 6H), 7.98 1H), 9.55 (s, 1H).

Example 7

N-[5-Chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2-trifluoromethylphenyl)urea(compound 7)

Yield 30.1%, m.p. 225°-226° C.

NMR (δ, ppm; DMSO-d₆)

7.28 (d, 1H), 7.33 (dt, 2H), 7.45-7.60 (m, 3H), 7.60-7.72 (m, 4H), 7.78(t, 1H), 8.32 (d, 1H), 9.80 (d, 1H).

Example 8

N-[5-Chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2-methoxyphenyl)urea(compound 8)

Yield 50.8%, m.p. 231°-232° C.

NMR (δ, ppm; DMSO-d₆) 3.85 (s, 3H), 6.88 (t, 1H), 7.00 (q, 2H), 7.25 (d,1H), 7.34 (dd, 1H), 7.47-7.57 (m, 3H), 7.63-7.66 (m, 2H), 8.01 (d, 1H),8.45 (s, 1H), 9.64 (s, 1H).

Example 9

N-[5-Chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2-methylthiophenyl)urea(compound 9)

Yield 14.1%, m.p. 189°-191° C.

NMR (δ, ppm; DMSO-d₆) 2.40 (s, 3H), 7.08-7.24 (m, 2H), 7.28-7.40 (m,2H), 7.47-7.54 (m, 4H), 7.63-7.74 (m, 3H), 8.35 (s, 1H), 9.76 (s, 1H).

Example 10

N-[5-Chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-2,4,6-trimethoxyphenyl)urea(compound 10)

Yield 41.0%, m.p. 228°-229° C.

NMR (δ, ppm; DMSO-d₆) 3.07 (s, 6H), 3.77 (s, 3H), 6.22 (s, 2H), 7.23 (d,1H), 7.30-7.36 (m, 2H), 7.46-7.49 (m, 2H), 7.53-7.54 (m, 1H), 7.60-7.62(m, 2H), 8.80 (br, 1H).

Example 11

N-[5-Chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2,6-dimethylphenyl)urea(compound 11)

Yield 48.2%, m.p. 249°-251° C.

NMR (δ, ppm; DMSO-d₆) 2.11 (s, 6H), 7.04 (s, 3H), 7.27 (d, 1H), 7.34(dd, 1H), 7.46 (t, 1H), 7.56 (t, 1H), 7.60-7.66 (m, 2H), 7.98 (s, 1H),9.25 (s, 1H).

Example 12

N-[5-Chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2,6-diethylphenyl)urea(compound 12)

Yield 47.6%, m.p. 222° C.

NMR (δ, ppm; DMSO-d₆) 1.08 (t, 6H), 2.47 (q, 4H), 7.06 (d, 2H), 7.15 (t,1H), 7.27 (d, 1H), 7.34 (dd, 1H), 7.45-7.63 (m, 3H), 7.61-7.66 (m, 2H),7.92 (s, 1H), 9.21 (s, 1H).

Example 13

N-[5-Chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 13)

Yield 50.5%, m.p. 242°-243° C.

NMR (δ, ppm; DMSO-d₆) 1.10 (d, 12H), 3.06 (m, 2H), 7.11 (d, 2H),7.20-7.35 (m, 3H), 7.48-7.53 (m, 3H), 7.62-7.66 (m, 2H), 7.91 (s, 1H),9.18 (s, 1H).

Example 14

N-[5-Chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2-ethyl-6-methylphenyl)urea(compound 14)

Yield 26.4%, m.p. 228°-230° C.

NMR (δ, ppm; DMSO-d₆) 1.07 (t, 3H), 2.10 (s, 3H), 2.49 (q, 2H),7.04-7.08 (m, 3H), 7.27-7.35 (m, 2H), 7.45-7.53 (m, 3H), 7.63-7.65 (m,2H), 7.94 (s, 1H), 9.23 (s, 1H).

Example 15

N-[5-Chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2-isopropyl-6-methylphenyl)urea(compound 15)

Yield 53.6%, m.p. 222°-223° C.

NMR (δ, ppm; DMSO-d₆) 1.09 (d, 6H), 2.10 (s, 3H), 3.08 (m, 1H),7.00-7.20 (m, 3H), 7.20-7.40 (m, 2H), 7.40-7.70 (m, 5H), 7.92 (s, 1H),9.27 (s, 1H).

Example 16

N-(2-t-Butyl-6-methylphenyl)-N'-[5-chloro-3-(2-chlorophenyl)benzofuran-2-yl]urea(compound 16)

Yield 21.8%, m.p. 218°-220° C.

NMR (δ, ppm; DMSO-d₆) 1.29 (s, 9H), 2.05 (s, 3H), 7.09-7.25 (m, 5H),7.32-7.65 (m, 5H), 7.77 (d, 1H), 9.25 (d, 1H).

Example 17

N-[5-Chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2,4-difluorophenyl)urea(compound 17)

Yield 44.1%, m.p. 222°-223° C.

NMR (δ, ppm; DMSO-d₆) 7.04 (t, 1H), 7.27-7.37 (m, 3H), 7.47-7.56 3H),7.64-7.67 (m, 2H), 7.92 (m, 1H), 8.75 (s, 1H), 9.36 (d, 1H).

Example 18

N-[5-Chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2,6-dibromophenyl)urea(compound 18)

Yield 19.6%, m.p. 217°-219° C.

NMR (δ, ppm; DMSO-d₆) 7.16-7.37 (m, 3H), 7.45-7.76 (m, 7H), 9.54 1H),9.35 (s, 1H).

Example 19

N-[5-chloro-3-(2-chlorophenyl)benzofuran-2-yl]-N'-(2-dimethylamino-6-methylphenyl)urea(compound

Yield 38.6%, m.p. 185°-186° C.

NMR (δ, ppm; DMSO-d₆) 2.05 (s, 3H), 2.53 (s, 6H), 6.83-6.89 (m, 2H),7.05 (m, 1H), 7.25 (d, 1H), 7.34 (m, 1H), 7.40-7.50 (m, 3H), 7.60-7.66(m, 2H), 7.80 (s, 1H), 9.36 (s, 1H).

Example 20

N-(2,6-Diisopropylphenyl)-N,-(5-methyl-3-phenylbenzofuran-2-yl)urea(compound 20)

Yield 15.5%, m.p. 223°-225° C.

NMR (δ, ppm; DMSO-d₆) 1.13 (d, 12H), 2.41 (s, 3H), 3.14 (m, 2H),7.12-7.23 (m, 4H), 7.48-7.52 (m, 5H), 7.68 (d, 2H), 7.96 (s, 1H), 8.34(s, 1H).

Example 21

N-[3-(2-Chlorophenyl)-5-methylbenzofuran-2-yl]-N'-(2,6-diethylphenyl)urea(compound 21)

To a stirred mixture of 430 mg of3-(2-chlorophenyl)-5-methylbenzofuran-2-carboxylic acid and 0.39 cc ofdiphenylphosphoryl azide in 6 cc of benzene was added dropwise 0.22 ccof triethylamine at room temperature. The resulting mixture was stirredat room temperature for 35 minutes and then heated under reflux for 15minutes. After cooling, 0.30 cc of 2,6-diethylaniline was added,followed by refluxing for 2 hours. After cooling, water was added to thereaction mixture and extracted with chloroform. The extract was driedover magnesium sulfate, and distilled to remove the solvent. The crudeproduct thus obtained was purified by a silica gel column chromatography(eluent: chloroform) to obtain 446 mg of compound 21.

Yield 68.7%, m.p. 214°-215° C.

NMR (δ, ppm; DMSO-d₆) 1.08 (t, 6H), 2.36 (s, 3H), 2.47 (q, 4H),7.05-7.18 (m, 5H), 7.44-7.50 (m, 3H), 7.53 (m, 1H), 7.61 (m, 1H), 7.85(s, 1H), 8.98 (s, 1H).

The compounds described in Examples 22 to 35 were obtained in the samemanner as in Example 21.

Example 22

N-[3-(2-Chlorophenyl)-5-methylbenzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 22)

Yield 52.1%, m.p. 232°-234° C.

NMR (δ, ppm; DMSO-d₆) 1.10 (d, 12H), 3.06 (m, 2H), 7.09-7.13 (m, 4H),7.22 (t, 1H), 7.44-7.48 (m, 3H), 7.52 (m, 1H), 7.62 (m, 1H), 7.84 (s,1H), 8.95 (s, 1H).

Example 23

N-[3-(2-Chlorophenyl)-5-methylbenzofuran-2-yl]-N'-(2,4-difluorophenyl)urea(compound 23)

Yield 72.7%, m.p. 179°-180° C.

NMR (δ, ppm; DMSO-d₆) 2.37 (s, 3H), 7.01-7.15 (m, 3H), 7.31 (t, 1H),7.45-7.53 (m, 4H), 7.64 (m, 1H), 7.93 (m, 1H), 8.72 (s, 1H), 9.15 (s,1H).

Example 24

N-[3-(2-Chlorophenyl)-5-ethylbenzofuran-2-yl]-N'-(2,6-diethylphenyl)urea(compound 24)

Yield 52.4%, m.p. 195°-197° C.

NMR (δ, ppm; DMSO-d₆) 1.06 (t, 6H), 1.17 (t, 3H), 2.47 (q, 4H), 2.66 (q,2H), 6.99-7.16 (m, 5H), 7.42-7.54 (m, 4H), 7.61 (m, 1H), 7.84 (s, 1H),8.97 (s, 1H).

Example 25

N-[3-(2-Chlorophenyl)-5-ethylbenzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 25)

Yield 47.6%, m.p. 233°-234° C.

NMR (δ, ppm; DMSO-d₆) 1.09 (d, 12H), 1.17 (t, 3H), 2.66 (q, 2H), 3.06(m, 2H), 7.10-7.22 (m, 5H), 7.44-7.54 (m, 4H), 7.54-7.61 (m, 1H), 7.83(s, 1H), 8.94 (s, 1H).

Example 26

N-[-3-(2-Chlorophenyl)-5-ethylbenzofuran-2-yl]-N'-(2,4-difluorophenyl)urea(compound 26)

Yield 39.6%, m.p. 167°-168 C.

NMR (δ, ppm; DMSO-d₆) 1.16 (t, 3H), 2.66 (q, 2H), 6.98-7.18 (m, 3H),7.30-7.32 (m, 1H), 7.46-7.54 (m, 4H), 7.63-7.64 (m, 1H), 7.86-7.94 (m,1H), 8.70 (s, 1H), 9.15 (d, 1H).

Example 27

N-[3-(2-Chlorophenyl)-5-n-hexylbenzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 27)

Yield 38.3%, m.p. 191°-192° C.

NMR (δ, ppm; DMSO-d₆) 0.84 (t, 3H), 1.11 (d, 12H), 1.21-1.36 (m, 6H),1.55 (m, 2H), 2.63 (t, 2H), 3.07 (m, 2H), 7.08-7.15 (m, 4H), 7.22 (t,1H), 7.44-7.49 (m, 3H), 7.54 (m, 1H), 7.62 (d, 1H), 7.85 (s, 1H), 8.95(s, 1H).

Example 28

N-[3-(2-Chlorophenyl)-5-n-hexylbenzofuran-2-yl]-N'-(2,4-difluorophenyl)urea(compound 28)

Yield 68.2%, m.p. 149°-150° C.

NMR (δ, ppm; DMSO-d₆) 0.83 (t, 3H), 1.2-1.35 (m, 6H), 1.55 (m, 2H), 2.63(t, 2H), 7.00-7.16 (m, 2H), 7.16 (d, 1H), 7.31 (m, 1H), 7.46-7.63 (m,4H), 7.65 (m, 1H), 7.90 (m, 1H), 8.71 (s, 1H), 9.14 (d, 1H).

Example 29

N-[3-(2-Chlorophenyl)-5-methoxybenzofuran-2-yl]-N'-(2,6-diethylphenyl)urea(compound 29)

Yield 57.0%, m.p. 220°-222° C.

NMR (δ, ppm; DMSO-d₆) 1.08 (t, 6H), 2.47 (q, 4H), 3.73 (s, 3H), 6.74 (d,1H), 6.90 (dd, 1H), 7.06 (d, 1H), 7.16 (t, 1H), 7.43-7.55 (m, 4H), 7.62(d, 1H), 7.86 (s, 1H), 8.99 (s, 1H).

Example 30

N-[3-(2-Chlorophenyl)-5-methoxybenzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 30)

Yield 37.7%, m.p. 216°-217° C.

NMR (δ, ppm; DMSO-d₆) 1.11 (d, 12H), 3.06 (m, 2H), 3.73 (s, 3H), 6.75(d, 1H), 6.90 (dd, 1H), 7.11 (d, 2H), 7.22 (t, 1H), 7.44-7.57 (m, 4H),7.63 (d, 1H), 7.85 (s, 1H), 8.96 (s, 1H).

Example 31

N-[3-(2-Chlorophenyl)-5-methoxybenzofuran-2-yl]-N'-(2,4-difluorophenyl)urea(compound 31)

Yield 42.8%, m.p. 190°-191° C.

NMR (δ, ppm; DMSO-d₆) 3.74 (s, 3H), 6.74 (d, 1H), 6.92 (dd, 1H), 7.04(dt, 1H), 7.31 (dt, 1H), 7.46-7.56 (m, 4H), 7.65 (m, 1H), 7.92 (m, 1H),8.72 (s, 1H), 9.17 (d, 1H).

Example 32

N-[3-(2-Chlorophenyl)-5-dimethylaminomethylbenzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 32)

Yield 39.7%, m.p. 197°-199° C.

NMR (δ, ppm; DMSO-d₆) 1.10 (d, 12H), 2.12 (s, 6H), 3.07 (m, 2H), 3.44(s, 2H), 7.11-7.25 (m, 5H), 7.45-7.65 (m, 5H), 7.86 (s, 1H), 8.98 (s,1H).

Example 33

N-[3-(2-Chlorophenyl)-5-(1-pyrrolidino)methylbenzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 33)

Yield 31.3%, m.p. 178°-179° C.

NMR (δ, ppm; DMSO-d₆) 1.10 (d, 12H), 1.66 (m, 4H), 2.40 (m, 4H), 3.07(m, 2H), 3.61 (s, 2H), 7.10-7.26 (m, 5H), 7.45-7.65 (m, 5H), 7.86 (s,1H), 8.98 (s, 1H).

Example 34

N-[3-(2-Chlorophenyl)-5-(1-morpholino)methylbenzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 34)

Yield 26.1%, m.p. 133°-1350° C.

NMR (δ, ppm; DMSO-d₆) 1.11 (d, 12H), 2.33 (s, 4H), 3.07 (m, 2H), 3.52(m, 6H), 7.10-7.27 (m, 5H), 7.45-7.62 (m, 5H), 7.85 (s, 1H), 8.98 (s,1H).

Example 35

N-[3-(2-Chlorophenyl)-5-(4-methyl-1-piperazino)methylbenzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 35)

Yield 16.1%, m.p. 136°-137° C.

NMR (δ, ppm; DMSO-d₆) 1.10 (d, 12H), 2.22 (s, 3H), 2.40 (brs, 8H), 3.06(m, 2H), 3.52 (m, 2H), 7.10-7.25 (m, 6H), 7.44-7.62 (m, 4H), 7.90 (s,1H), 9.04 (s, 1H).

Example 36

N-[3-(2-Chlorophenyl)-5,6-dimethylbenzofuran-2-yl]-N'-(2,6-dimethylphenyl)urea(compound 36)

To a stirred mixture of 301 mg of3-(2-chlorophenyl)-5,6-dimethylbenzofuran-2-carboxylic acid and 0.26 ccof diphenylphosphoryl azide in 5 cc of benzene was added dropwise 0.14cc of triethylamine at room temperature. The resulting mixture wasstirred at room temperature for 15 minutes and then heated under refluxfor 15 minutes. After cooling, 0.14 cc of 2,6-dimethylaniline was added,followed by refluxing for 2 hours. After cooling, water was added to thereaction mixture and extracted with chloroform. The extract was driedover magnesium sulfate, and distilled to remove the solvent. The crudeproduct thus obtained was purified by a silica gel column chromatography(eluent: chloroform) to obtain 279 mg of compound 36.

Yield 66.6%, m.p. 252°-254° C.

NMR (δ, ppm; DMSO-d₆) 2.11 (s, 6H), 2.26 (s, 3H), 2.33 (s, 3H), 7.05 (d,4H), 7.37 (s, 1H), 7.43 (m, 2H), 7.54 (m, 1H), 7.62 (m, 1H), 7.89 (s,1H), 8.90 (br, 1H).

The compounds described in Examples 37 to 59 were obtained in the samemanner as in Example 36.

Example 37

N-[3-(2-Chlorophenyl)-5,6-dimethylbenzofuran-2-yl]-N'-(2,6-diethylphenyl)urea(compound 37)

Yield 62.6%, m.p. 228°-230° C.

NMR (δ, ppm; DMSO-d₆) 1.08 (t, 6H), 2.26 (s, 3H), 2.33 (s, 3H), 2.47 (q,4H), 7.06 (d, 3H), 7.14 (t, 1H), 7.37 (s, 1H), 7.45 (m, 2H), 7.52 (m,1H), 7.61 (m, 1H), 7.81 (s, 1H), 8.88 (s, 1H).

Example 38

N-[3-(2-Chlorophenyl)-5,6-dimethylbenzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 38)

Yield 41.1%, m.p. 249°-250° C.

NMR (δ, ppm; DMSO-d₆) 1.09 (d, 12H), 2.26 (s, 3H), 2.33 (s, 3H), 3.06(m, 2H), 7.09 (m, 3H), 7.21 (t, 1H), 7.37 (s, 1H), 7.44 (m, 2H), 7.50(m, 1H), 7.61 (dd, 1H), 7.81 (s, 1H), 8.85 (s, 1H).

Example 39

N-[2-[3-(2-Chlorophenyl)-5,6-dimethylbenzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 39)

Yield 53.5%, m.p. 218°-221° C.

NMR (δ, ppm; DMSO-d₆) 1.10 (d, 6H), 2.10 (s, 3H), 2.26 (s, 3H), 2.33 (s,3H), 3.08 (m, 1H), 7.06 (m, 2H), 7.12 (m, 2H), 7.37 (s, 1H), 7.43 (m,2H), 7.52 (m, 1H), 7.60 (m, 1H), 7.84 (s, 1H), 8.90 (s, 1H).

Example 40

N-[3-(2-Chlorophenyl)-5,6-dimethylbenzofuran-2-yl]-N'-(2,4-difluorophenyl)urea(compound 40)

Yield 54.8%, m.p. 205°-207° C.

NMR (δ, ppm; DMSO-d₆) 2.26 (s, 3H), 2.33 (s, 3H), 7.02 (m, 2H), 7.30(dt, 1H), 7.38 (s, 1H), 7.47 (m, 4H), 7.61 (m, 1H), 7.91 (m, 1H), 8.69(s, 1H), 9.06 (d, 1H).

Example 41

N-[3-(2-Chlorophenyl)-5,7-dimethylbenzofuran-2-yl]-N'-(2,6-dimethylphenyl)urea(compound 41)

Yield 65.4%, m.p. 243°-244° C.

NMR (δ, ppm; DMSO-d₆) 2.10 (s, 6H), 2.32 (s, 3H), 2.45 (s, 3H), 6.90 (s,1H), 6.95 (s, 1H), 7.03 (s, 3H), 7.43 (m, 2H), 7.51 (m, 1H), 7.60 (m,1H), 7.90 (s, 1H), 9.00 (br, 1H).

Example 42

N-[3-(2-Chlorophenyl)-5,7-dimethylbenzofuran-2-yl]-N'-(2,6-diethylphenyl)urea(compound 42)

Yield 63.7%, m.p. 223°-2240° C.

NMR (δ, ppm; DMSO-d₆) 1.07 (s, 6H), 2.32 (s, 3H), 2.45 (s, 3H), 2.47 (q,4H), 6.90 (s, 1H), 6.95 (s, 1H), 7.05 (d, 2H), 7.15 (t, 1H), 7.43 (m,2H), 7.50 (m, 1H), 7.62 (m, 1H), 7.86 (s, 1H), 8.98 (s, 1H).

Example 43

N-[3-(2-Chlorophenyl)-5,7-dimethylbenzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 43)

Yield 84.2%, m.p. 208°-210° C.

NMR (δ, ppm; DMSO-d₆) 1.09 (d, 12H), 2.32 (s, 3H), 2.45 (s, 3H), 3.06(m, 2H), 6.90 (s, 1H), 6.95 (s, 1H), 7.10 (d, 2H), 7.21 (t, 1H), 7.43(m, 2H), 7.50 (m, 1H), 7.60 (m, 1H), 7.85 (s, 1H), 8.96 (s, 1H).

Example 44

N-[3-(2-Chlorophenyl)-5,7-dimethylbenzofuran-2-yl]-N'-(2-isopropyl-6-methylphenyl)urea(compound 44)

Yield 69.4%, m.p. 227°-228° C.

NMR (δ, ppm; DMSO-d₆) 1.08 (d, 6H), 2.08 (s, 3H), 2.32 (s, 3H), 2.45 (s,3H), 3.08 (m, 1H), 6.89 (s, 1H), 6.95 (s, 1H), 7.03 (m, 1H), 7.11 (m,2H), 7.43 (m, 2H), 7.51 (m, 1H), 7.60 (m, 1H), 7.86 (s, 1H), 9.00 (s,1H).

Example 45

N-[3-(2-Chlorophenyl)-5,7-dimethylbenzofuran-2-yl]-N'-(2,4,6-trimethylphenyl)urea(compound 45)

Yield 73.2%, m.p. 248°-249° C.

NMR (δ, ppm; DMSO-d₆) 2.06 (s, 6H), 2.20 (s, 3H), 2.32 (s, 3H), 2.44 (s,3H), 6.84 (s, 2H), 6.90 (s, 1H), 6.95 (s, 1H), 7.42 (m, 2H), 7.52 (m,1H), 7.60 (m, 1H), 7.80 (s, 1H), 8.97 (br, 1H).

Example 46

N-[3-(2-Chlorophenyl)-5,7-dimethylbenzofuran-2-yl]-N'-(2,4-difluorophenyl)urea(compound 46)

Yield 71.6%, m.p. 212°-214° C.

NMR (δ, ppm; CDCl₃) 2.38 (s, 3H), 2.55 (s, 3H), 6.80 (s, 1H), 6.83-6.92(m, 2H), 6.97 (d, 2H), 7.36-7.42 (m, 2H), 7.44-7.48 (m, 1H), 7.52-7.58(m, 1H), 8.07-8.17 (m, 2H).

Example 47

N-[3-(2-Chlorophenyl)-5,7-dimethylbenzofuran-2-yl]-N'-(2,6-difluorophenyl)urea(compound 47)

Yield 59.7%, m.p. 223°-224° C.

NMR (δ, ppm; DMSO-d₆) 2.32 (s, 3H), 2.44 (s, 3H), 6.90 (s, 1H), 6.97 (s,1H), 7.13 (m, 2H), 7.31 (m, 1H), 7.45 (m, 2H), 7.52 (m, 1H), 7.63 (m,1H), 8.35 (s, 1H), 9.14 (s, 1H).

Example 48

N-[3-(2-Chlorophenyl)-5,7-dimethylbenzofuran-2-yl]-N'-(2,4,6-trifluorophenyl)urea(compound 48)

Yield 60.7%, m.p. 235°-238° C.

NMR (δ, ppm; DMSO-d₆) 2.32 (s, 3H), 2.44 (s, 3H), 6.90 (s, 1H), 6.97 (s,1H), 7.24 (t, 2H), 7.44 (m, 2H), 7.49 (m, 1H), 7.61 (m, 1H), 8.27 (s,1H), 9.20 (s, 1H).

Example 49

N-[3-(2-Chlorophenyl)-5,7-dimethylbenzofuran-2-yl]-N'-(2,6-dichlorophenyl)urea(compound 49)

Yield 49.2%, m.p. 232°-236° C.

NMR (δ, ppm; DMSO-d₆) 2.32 (s, 3H), 2.45 (s, 3H), 6.91 (s, 1H), 6.97 (s,1H), 7.30 (t, 1H), 7.40-7.56 (m, 5H), 7.60 (dd, 1H), 8.46 (s, 1H), 9.15(s, 1H).

Example 50

N-[3-(2-Chlorophenyl)-5,7-dimethylbenzofuran-2-yl]-N'-(4-dimethylaminophenyl)urea(compound 50)

Yield 60.9%, m.p. 240°-242° C.

NMR (δ, ppm; DMSO-d₆) 2.32 (s, 3H), 2.45 (s, 3H), 2.82 (s, 6H), 6.66 (d,2H), 6.88 (s, 1H), 6.95 (s, 1H), 7.18 (d, 2H), 7.45 (m, 2H), 7.51 (m,1H), 7.60 (m, 1H), 8.47 (s, 1H), 8.64 (s, 1H).

Example 51

N-[3-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[f]benzofuran-2-yl]-N'-(2,6-dimethylphenyl)urea(compound 51)

Yield 72.7%, m.p. 247°-250° C.

NMR (δ, ppm; DMSO-d₆) 2.05 (m, 2H), 2.11 (s, 6H), 2.88 (t, 2H), 2.95 (t,2H), 7.04 (s, 3H), 7.09 (s, 1H), 7.43 (m, 3H), 7.51 (m, 1H), 7.60 (m,1H), 7.88 (s, 1H), 8.91 (br, 1H).

Example 52

N-[3-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[f]benzofuran-2-yl]-N'-(2,6-diethylphenyl)urea(compound 52)

Yield 71.8%, m.p. 264°-266° C.

NMR (δ, ppm; DMSO-d₆) 1.08 (t, 6H), 2.04 (m, 2H), 2.47 (q, 4H), 2.87 (t,2H), 2.95 (t, 2H), 7.07 (t, 3H), 7.14 (t, 1H), 7.43 (m, 3H), 7.51 (m,1H), 7.61 (m, 1H), 7.81 (s, 1H), 8.89 (s, 1H).

Example 53

N-[3-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[f]benzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 53)

Yield 67.1%, m.p. 245°-247° C.

NMR (δ, ppm; DMSO-d₆) 1.09 (d, 12H), 2.05 (m, 2H), 2.88 (t, 2H), 2.95(t, 2H), 3.06 (m, 2H), 7.11 (d, 3H), 7.20 (t, 1H), 7.44 (m, 3H), 7.51(m, 1H), 7.61 (d, 1H), 7.81 (s, 1H), 8.86 (s, 1H).

Example 54

N-[3-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[f]benzofuran-2-yl]-N'-(2,4,6-trimethylphenylphenyl)urea(compound 54)

Yield 67.1%, m.p. 245°-247° C.

NMR (δ, ppm; DMSO-d₆) 2.04 (m, 2H), 2.06 (s, 6H), 2.20 (s, 3H), 2.87 (t,2H), 2.95 (t, 2H), 6.84 (s, 2H), 7.09 (s, 1H), 7.43 (m, 3H), 7.50 (m,1H), 7.60 (m, 1H), 7.78 (s, 1H), 8.90 (br, 1H).

Example 55

N-[3-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[f]benzofuran-2-yl]-N'-(2,4-difluorophenyl)urea(compound 55)

Yield 65.3%, m.p. 208°-209° C.

NMR (δ, ppm; DMSO-d₆) 2.06 (m, 2H), 2.88 (t, 2H), 2.96 (t, 2H), 7.03(dt, 1H), 7.08 (s, 1H), 7.30 (dt, 1H), 7.40-7.55 (m, 4H), 7.63 (m, 1H),7.92 (m, 1H), 8.69 (s, 1H), 9.07 (s, 1H).

Example 56

N-[3-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[f]benzofuran-2-yl]-N'-(2,4,6-trifluorophenyl)urea(compound 56)

Yield 51.8%, m.p. 244°-247° C.

NMR (δ, ppm; DMSO-d₆) 2.05 (m, 2H), 2.88 (t, 2H), 2.96 (t, 2H), 7.10 (s,1H), 7.24 (t, 2H), 7.40-7.50 (m, 3H), 7.51 (m, 1H), 7.62 (d, 1H), 8.28(s, 1H), 9.15 (s, 1H).

Example 57

N-[5-Chloro-3-(2-fluorophenyl)benzofuran-2-yl]-N'-(2,6-diethylphenyl)urea(compound 57)

Yield 24.1%, m.p. 237°-238° C.

NMR (δ, ppm; DMSO-d₆) 1.10 (t, 6H), 2.49 (q, 4H), 7.06-7.17 (m, 3H),7.31-7.50 (m, 5H), 7.61-7.66 (m, 2H), 7.99 (s, 1H), 9.19 (s, 1H).

Example 58

N-[5-Chloro-3-(2-fluorophenyl)benzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 58)

Yield 27.0%, m.p. 247°-249° C.

NMR (δ, ppm; DMSO-d₆) 1.11 (d, 12H), 3.08 (m, 2H), 7.11-7.22 (m, 3H),7.33-7.50 (m, 5H), 7.61-7.66 (m, 2H), 7.99 (s, 1H), 9.15 (s, 1H).

Example 59

N-[5-Chloro-3-(2-fluorophenyl)benzofuran-2-yl]-N'-(2,4-difluorophenyl)urea (compound 59)

Yield 31.5%, m.p. 265°-266° C.

NMR (δ, ppm; DMSO-d₆) 6.98-7.04 (m, 1H), 7.29-7.51 (m, 6H), 7.61-7.67(m, 2H), 7.82-7.91 (m, 1H), 8.82 (s, 1H), 9.36 (s, 1H).

Example 60

N-[5-Chloro-3-(2-methylphenyl)benzofuran-2-yl]-N'-(2,6-diethylphenyl)urea(compound 60)

To stirred a mixture of 573 mg of5-chloro-3(2-methylphenyl)benzofuran-2-carboxylic acid and 0.47 cc ofdiphenylphosphoryl azide in 6 cc of benzene was added dropwise 0.30 ccof triethylamine at room temperature. The resulting mixture was stirredat room temperature for 30 minutes and then heated under reflux for 15minutes. After cooling, 0.36 cc of 2,6-diethylaniline was added,followed by refluxing for 2 hours. After cooling, water was added to thereaction mixture and was extracted with chloroform. The extract wasdried over magnesium sulfate, and distilled to remove the solvent. Thecrude product thus obtained was purified by a silica gel columnchromatography (eluent: chloroform) to obtain 219 mg of compound 60.

Yield 25.3%, m.p. 233°-234° C.

NMR (δ, ppm; DMSO-d₆) 1.06 (t, 6H), 2.22 (s, 3H), 2.45 (q, 4H),7.02-7.20 (m, 4H), 7.29-7.37 (m, 5H), 7.64 (d, 1H), 7.89 (s, 1H), 8.99(s, 1H).

The compounds described in Examples 61 to 63 were obtained in the samemanner as in Example 60.

Example 61

N-[5-Chloro-3-(2-methylphenyl)benzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 61)

Yield 21.8%, m.p. 254°-256° C.

NMR (δ, ppm; DMSO-d₆) 1.10 (d, 12H), 2.22 (s, 3H), 3.02 (m, 2H),7.10-7.22 (m, 4H), 7.31-7.38 (m, 5H), 7.64 (d, 1H), 7.88 (s, 1H), 8.94(s, 1H).

Example 62

N-[5-Chloro-3-(2-methylthiophenyl)benzofuran-2-yl]-N'-(2,6-diethylphenyl)urea(compound 62)

Yield 41.9%, m.p. 208°-210° C.

NMR (δ, ppm; DMSO-d₆) 1.08 (t, 6H), 2.41 (s, 3H), 2.48 (q, 4H),7.05-7.30 (m, 7H), 7.32-7.43 (m, 2H), 7.62 (d, 1H), 7.84 (s, 1H), 8.98(s, 1H).

Example 63

N-[5-Chloro-3-(2-methylthiophenyl)benzofuran-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 63)

Yield 43.8%, m.p. 213°-215° C.

NMR (δ, ppm; DMSO-d₆) 1.09 (d, 12H), 2.42 (s, 3H), 3.08 (m, 2H),7.11-7.13 (m, 2H), 7.19-7.36 (m, 5H), 7.44-7.49 (m, 2H), 7.62 (d, 1H),7.83 (s, 1H), 8.94 (s, 1H).

Example 64

N-[5-Chloro-3-(2-chlorophenyl)-1-benzothiophen-2-yl]-N'-(2,6-dimethylphenyl)urea(compound 64)

To a stirred mixture of 400 mg of5-chloro-3-(2-chlorophenyl)-1-benzothiophen-2-carboxylic acid and 0.27cc of diphenylphosphoryl azide in 3 cc of benzene was added dropwise0.175 cc of triethylamine at room temperature. The resulting mixture wasstirred at room temperature for 15 minutes and then heated under refluxfor 20 minutes. After cooling, 0.16 cc of 2,6-dimethylaniline was addedand the resulting mixture was stirred at room temperature for 30minutes, followed by refluxing for 1 hour. After cooling, water wasadded to the reaction mixture and was extracted with chloroform. Theextract was dried over magnesium sulfate and distilled to remove thesolvent. The crude product thus obtained was purified by a silica gelcolumn chromatography (eluent: chloroform/hexane=7/3) to obtain 175 mgof compound 64.

Yield 32.2%, m.p. 203°-204° C.

NMR (δ, ppm; DMSO-d₆) 2.27 (s, 6H), 6.89 (d, 1H), 7.07 (s, 3H), 7.20(dd, 1H), 7.50-7.61 (m, 3H), 7.71-7.79 (m, 1H), 7.87 (d, 1H), 8.31 (s,1H), 9.10 (s, 1H).

The compounds described in Examples 65 to 86 were obtained in the samemanner as in Example 64.

Example 65

N-[5-Chloro-3-(2-chlorophenyl)-1-benzothiophen-2-yl]-N'-(2,6-diethylphenyl)urea(compound 65)

Yield 39.0%, m.p. 145°-147° C.

NMR (δ, ppm; DMSO-d₆) 1.11 (t, 6H), 2.52 (q, 4H), 6.91 (d, 1H), 7.10 (s,1H), 7.13 (s, 1H), 7.17 (s, 1H), 7.21 (dd, 1H), 7.54-7.79 (m, 3H), 7.87(d, 1H), 8.25 (s, 1H), 9.12 (s, 1H).

Example 66

N-[5-Chloro-3-(2-chlorophenyl )-1-benzothiophen-2-yl]-N'-(2,6-diisopropylphenyl)urea (compound 66)

Yield 29.8%, m.p. 126°-127° C.

NMR (δ, ppm; DMSO-d₆) 1.11 (d, 12H), 3.05 (m, 2H), 6.90 (d, 1H), 7.13(d, 1H), 7.17 (s, 1H), 7.22 (s, 1H), 7.27 (d, 1H), 7.53-7.61 (m, 3H),7.71-7.79 (m, 1H), 7.87 (d, 1H), 8.20 (s, 1H), 9.10 (s, 1H).

Example 67

N-[5-Chloro-3-(2-chlorophenyl)-1-benzothiophen-2-yl]-N'-(2-isopropyl-6-methylphenyl)urea(compound

Yield 28.9%, m.p. 219°-220° C.

NMR (δ, ppm; DMSO-d₆) 1.10 (d, 6H), 2.16 (s, 3H), 3.07 (m, 1H), 6.90 (d,1H), 7.05-7.25 (m, 4H), 7.50-7.62 (m, 3H), 7.71-7.79 (m, 1H), 7.87 (d,1H), 8.26 (s, 1H), 9.12 (s, 1H).

Example 68

N-[5-Chloro-3-(2-chlorophenyl)-1-benzothiophen-2-yl]-N'-(2,4-difluorophenyl)urea(compound 68)

Yield 39.1%, m.p. 232°-233° C.

NMR (δ, ppm; CDCl₃) 6.75-6.88 (m, 2H), 7.11 (d, 1H), 7.21 (dd, 1H),7.36-7.41 (m, 3H), 7.52-7.56 (m, 1H), 7.59 (s, 1H), 7.68 (d, 1H), 7.82(s, 1H), 7.92-8.01 (m, 1H).

Example 69

N-[5-Chloro-3-(2-chlorophenyl)-1-benzothiophen-2-yl]-N'-(2,6-difluorophenyl)urea (compound 69)

Yield 48.2%, m.p. 239°-240° C.

NMR (δ, ppm; CDCl₃) 6.86 (t, 2H), 7.00 (d, 1H), 7.09 (dd, 1H), 7.01-7.13(m, 1H), 7.36-7.42 (m, 3H), 7.53-7.57 (m, 1H), 7.59 (d, 1H), 8.37 (s,1H), 8.77 (s, 1H).

Example 70

N-[5-Chloro-3-(2-chlorophenyl )-1-benzothiophen-2-yl]-N'-(2,4,6-trifluorophenyl)urea (compound

Yield 37.4%, m.p. 230°-231° C.

NMR (δ, ppm; CDCl₃) 6.67 (t, 2H), 7.12 (d, 1H), 7.20 (dd, 2H), 7.28-7.36(m, 4H), 7.65 (d, 1H), 7.95 (s, 1H).

Example 71

N-[5-Chloro-3-(2-chlorophenyl)-1-benzothiophen-2-yl]-N'-(2,6-dichlorophenyl)urea (compound 71)

Yield 31.8%, m.p. 186°-187° C.

NMR (δ, ppm; DMSO-d₆) 6.91 (d, 1H), 7.22 (dd, 1H), 7.29-7.38 (m, 1H),7.50-7.65 (m, 5H), 7.71-7.81 (m, 1H), 7.90 (d, 1H), 8.76 (s, 1H), 9.28(s, 1H).

Example 72

N-[3-(2-Chlorophenyl)-5-methyl-1-benzothiophen-2-yl]-N'-(2,6-diethylphenyl)urea(compound 72)

Yield 81.3%, m.p. 125°-126° C.

NMR (δ, ppm; DMSO-d₆) 1.11 (t, 6H), 2.30 (s, 3H), 2.53 (q, 4H), 6.80 (s,1H), 7.02 (d, 1H), 7.08-7.22 (m, 3H), 7.49-7.12 (m, 3H), 7.70 (d, 1H),7.72-7.80 (m, 1H), 8.21 (s, 1H), 8.93 (s, 1H).

Example 73

N-[3-(2-Chlorophenyl)-5-methyl-1-benzothiophen-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 73)

Yield 79.3%, m.p. 193°-194° C.

NMR (δ, ppm; DMSO-d₆) 1.10 (d, 12H), 2.30 (s, 3H), 3.06 (m, 2H), 6.80(s, 1H), 7.02 (d, 1H), 7.17 (d, 2H), 7.25 (d, 1H), 7.50-7.75 (m, 3H),7.69 (d, 1H), 7.73-7.80 (m, 1H), 8.17 (s, 1H), 8.92 (s, 1H).

Example 74

N-[3-(2-Chlorophenyl)-5-methyl-1-benzothiophen-2-yl]-N'-(2-isopropyl-6-methylphenyl)urea(compound

Yield 68.8%, m.p. 203°-205° C.

NMR (δ, ppm; DMSO-d₆) 1.12 (d, 6H), 2.17 (s, 3H), 2.30 (s, 3H), 3.08 (m,1H), 6.79 (s, 1H), 7.02 (d, 1H), 7.06-7.18 (m, 3H), 7.50-7.62 (m, 3H),7.70 (d, 1H), 7.72-7.80 (m, 1H), 8.22 (s, 1H), 8.94 (s, 1H).

Example 75

N-[3-(2-Chlorophenyl)-5-methyl-1-benzothiophen-2-yl]-N'-(2,4-difluorophenyl)urea (compound 75)

Yield 79.3%, m.p. 186°-187° C.

NMR (δ, ppm; CDCl₃) 2.30 (s, 3H), 6.72-6.88 (m, 2H), 6.97-7.07 (m, 2H),7.13 (dd, 1H), 7.18 (s, 1H), 7.33-7.42 (m, 3H), 7.47-7.57 (m, 1H), 7.69(d, 1H), 7.80-7.95 (m, 1H).

Example 76

N-[3-(2-Chlorophenyl)-5-isopropyl-1-benzothiophen-2-yl]-N'-(2,6-diethylphenyl)urea(compound 76) Yield 69.7%, m.p. 135°-137° C.

NMR (δ, ppm; DMSO-d₆) 1.11 (t, 6H), 1.16 (d, 6H), 2.53 (q, 4H), 2.87 (m,1H), 6.85 (s, 1H), 7.07-7.22 (m, 4H), 7.50-7.64 (m, 3H), 7.70-7.80 (m,2H), 8.21 (s, 1H), 8.92 (s, 1H).

Example 77

N-[3-(2-chlorophenyl)-5-isopropyl-1-benzothiophen-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 77)

Yield 54.6%, m.p. 147°-149° C.

NMR (δ, ppm; DMSO-d₆) 1.05-1.25 (m, 18H), 2.86 (m, 1H), 3.08 (m, 2H),6.85 (s, 1H), 7.08-7.30 (m, 4H), 7.52-7.65 (m, 3H), 7.70-7.81 (m, 2H),8.18 (s, 1H), 8.91 (s, 1H).

Example 78

N-[3-(2-Chlorophenyl )-5-isopropyl-1-benzothiophen-2-yl]-N'-(2,4-difluorophenyl)urea (compound 78)

Yield 67.5%, m.p. 221°-222° C.

NMR (δ, ppm; DMSO-d₆) 1.16 (d, 6H), 2.87 (m, 1H), 6.83 (s, 1H), 7.08

(dt, 1H), 7.15 (d, 1H), 7.33 (dt, 1H), 7.45-7.65 (m, 3H), 7.73-7.81 (m,2H), 8.10-8.21 (m, 1H), 9.13 (s, 1H), 9.26 (s, 1H).

Example 79

N-[3-(2-Chlorophenyl)-5,6-dimethyl-1-benzothiophen-2-yl]-N'-(2,4-dimethylphenyl)urea(compound 79)

Yield 78.3%, m.p. 145°-147° C.

NMR (δ, ppm; DMSO-d₆) 2.14 (s, 3H), 2.20 (s, 3H), 2.23 (s, 3H), 2.29 (s,3H), 6.74 (s, 1H), 6.65-7.00 (m, 2H), 7.45-7.75 (m, 6H), 8.36 (s, 1H),9.50 (s, 1H).

Example 80

N-[3-(2-Chlorophenyl)-5,6-dimethyl-1-benzothiophen-2-yl]-N'-(2,6-diethylphenyl)urea(compound 80)

Yield 97.3%, m.p. 205°-206° C.

NMR (δ, ppm; DMSO-d₆) 1.10 (t, 6H), 2.22 (s, 3H), 2.30 (s, 3H), 2.53 (q,4H), 6.80 (s, 1H), 7.08-7.26 (m, 3H), 7.45-7.65 (m, 4H), 7.70-7.83 (m,1H), 8.20 (s, 1H ), 8.88 (s, 1H ).

Example 81

N-(3-(2-Chlorophenyl)-5,6-dimethyl-1-benzothiophen-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound

Yield 88.4%, m.p. 205°-207° C.

NMR (δ, ppm; DMSO-d₆) 1.10 (d, 12H), 2.21 (s, 3H), 2.29 (s, 3H), 3.09(m, 2H), 6.80 (s, 1H), 7.13-7.32 (m, 3H), 7.50-7.63 (m, 4H), 7.72-7.80(m, 1H), 8.15 (s, 1H), 8.87 (s, 1H).

Example 82

N-[3-(2-Chlorophenyl)-5,6-dimethyl-1-benzothiophen-2-yl]-N'-(2-isopropyl-6-methylphenyl)urea(compound 82)

Yield 94.3%, m.p. 205°-206° C.

NMR (δ, ppm; DMSO-d₆) 1.13 (d, 6H), 2.16 (s, 3H), 2.20 (s, 3H), 2.30 (s,3H), 3.10 (m, 1H), 6.79 (s, 1H), 7.05-7.20 (m, 3H), 7.45-7.63 (m, 4H),7.60-7.72 (m, 1}{), 8.21 (s, 1H), 8.89 (s, 1H).

Example 83

N-[3-(2-Chlorophenyl)-5,6-dimethyl-1-benzothiophen-2-yl]-N'-(2-dimethylamino-6-methylphenyl)urea(compound 83)

Yield 82.8%, m.p. 204°-206° C.

NMR (δ, ppm; DMSO-₆) 2.15 (s, 3H), 2.20 (s, 3H), 2.29 (s, 3H), 2.56 (s,6H), 6.76 (s, 1H), 6.89 (d, 2H), 7.07 (t, 1H), 7.43-7.48 (m, 1H),7.53-7.58 (m, 3H), 7.69-7.73 (m, 1H), 8.24 (s, 1H), 9.09 (s, 1H).

Example 84

N-[3-(2-Chlorophenyl)-5,6-dimethyl-1-benzothiophen-2-yl]-N'-(2,4-difluorophenyl)urea(compound 84)

Yield 86.0%, m.p. 147°-150° C.

NMR (δ, ppm; CDCl₃) 2.25 (s, 3H), 2.33 (s, 3H), 6.70-6.92 (m, 3H),7.37-7.47 (m, 3H), 7.52-7.63 (m, 2H), 8.24 (dt, 1H), 8.56 (s, 1H), 8.70(s, 1H).

Example 85

N-[3-(2-Chlorophenyl)-5,6-dimethyl-1-benzothiophen-2-yl]-N'-(2-fluoro-4-methylphenyl)urea(compound 85)

Yield 61.2%, m.p. 207°-208° C.

NMR (δ, ppm; DMSO-₆) 2.21 (s, 3H), 2.27 (s, 3H), 2.30 (s, 3H), 6.77 (s,1H), 6.95-7.08 (m, 2H), 7.45 (m, 5H), 8.02 (t, 1H), 9.02 (s, 1H), 9.18(s, 1H).

Example 86

N-[3-(2-Chlorophenyl)-5,6-dimethyl-1-benzothiophen-2-yl]-N'-(2,4,6-trimethoxyphenyl)urea(compound 86)

Yield 80.5%, m.p. 215°-216° C.

NMR (δ, ppm; CDCl₃) 2.27 (s, 3H), 2.35 (s, 3H), 3.61 (s, 6H), 3.81 (s,3H), 5.81 (s, 1H), 6.02 (s, 2H), 6.92 (s, 1H), 7.22-7.37 (m, 4H),7.42-7.49 (m, 1H), 7.54 (s, 1H).

Example 87

N-[3-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]-N'-(2,6-dimethylphenyl)urea(compound 87)

To a stirred mixture of 400 mg of3-(2-chlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophene-2-carboxylicacid and 0.27 cc of diphenylphosphoryl azide in 5 cc of benzene wasadded dropwise 0.175 cc of triethylamine at room temperature. Theresulting mixture was stirred at room temperature for 15 minutes andthen heated under reflux for 30 minutes. After cooling, 0.155 cc of2,6-dimethylaniline was added, followed by refluxing for 2 hours. Aftercooling, water was added to the reaction mixture and the desiredcompound was extracted with chloroform. The extract was dried overmagnesium sulfate, and distilled to remove the solvent. The crudeproduct thus obtained was purified by a silica gel column chromatography(eluent: ethyl acetate/hexane=15/85) to obtain 454 mg of compound 87.

Yield 84.6%, m.p. 236°-237° C.

NMR (δ, ppm; DMSO-₆) 2.05 (m, 2H), 2.18 (s, 6H), 2.85 (t, 2H), 2.94 (t,2H), 6.90-7.50 (m, 4H), 7.20-7.50 (m, 4H), 7.55 (s, 1H).

The compounds described in Examples 88 to 101 were obtained in the samemanner as in Example 87.

Example 88

N-[3-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]-N'-(2,6-diethylphenyl)urea(compound 88)

Yield 98.5%, m.p. 205°-206° C.

NMR (δ, ppm; DMSO-₆) 1.11 (t, 6H), 2.01 (m, 2H), 2.53 (q, 4H), 2.82 (t,2H), 2.91 (t, 2H), 6.83 (s, 1H), 7.08-7.25 (m, 3H), 7.45-7.80 (m, 5H),8.17 (s, 1H), 8.86 (s, 1H).

Example 89

N-[3-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 89)

Yield 72.9%, m.p. 213°-214° C.

NMR (δ, ppm; DMSO-₆) 1.10 (d, 12H), 2.00 (m, 2H), 2.81 (t, 2H), 2.88 (t,2H), 3.07 (m, 2H), 6.81 (s, 1H), 7.12-7.30 (m, 3H), 7.48-7.60 (m, 3H),7.63 (s, 1H), 7.72-7.78 (m, 1H), 8.12 (s, 1H), 8.83 (s, 1H).

Example 90

N-[3-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]-N'-(2-isopropyl-6-methylphenyl)urea(compound 90)

Yield 79.1%, m.p. 200°-202° C.

NMR (δ, ppm; DMSO-₆) 1.13 (d, 6H), 2.01 (m, 2H), 2.16 (s, 3H), 2.82 (t,2H), 2.91 (t, 2H), 3.08 (m, 1H), 6.83 (s, 1H), 7.05-7.20 (m, 3H),7.45-7.75 (m, 5H), 8.19 (s, 1H), 8.88 (s, 1H).

Example 91

N-[3-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]-benzothiophen-2-yl[-N'-(2-dimethylamino-6-methylphenyl)urea (compound 91)

Yield 79.5%, m.p. 192°-194° C.

NMR (δ, ppm; DMSO-₆) 2.01 (m, 2H), 2.15 (s, 3H), 2.56 (s, 6H), 2.82 (t,2H), 2.91 (t, 2H), 6.81 (s, 1H), 6.88 (d, 2H), 7.07 (t, 1H), 7.44-7.72(m, 5H), 8.24 (d, 20 1H), 9.08 (s, 1H).

Example 92

N-(3-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]-N'-(2,4-difluorophenyl)urea(compound 92)

Yield 80.6%, m.p. 129°-130° C.

NMR (δ, ppm; CDCl₃) 2.01 (m, 2H), 2.90 (t, 2H), 2.99 (t, 2H), 6.72-6.85(m, 2H), 7.03 (s, 1H), 7.25-7.55 (m, 6H), 7.62 (s, 1H), 7.87-7.97 (m,1H).

Example 93

N-[3-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]-N'-(2,6-difluorophenyl)urea(compound 93)

Yield 75.2%, m.p. 252°-253° C.

NMR (δ, ppm; CDCl₃) 2.01 (m, 2H), 2.82 (t, 2H), 2.90 (t, 2H), 6.82-6.92(m, 3H), 7.00-7.11 (m, 1H), 7.32-7.41 (m, 3H), 7.51-7.57 (m, 2H), 8.28(s, 1H), 8.56 (s, 1H).

Example 94

N-[3-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]-N'-(2,4,6-trifluorophenyl)urea(compound 94)

Yield 62.3%, m.p. 235°-236° C.

NMR (δ, ppm; CDCl₃) 2.01 (m, 2H), 2.90 (t, 2H), 3.00 (t, 2H), 6.50 (s,1H), 6.65 (t, 2H), 7.05 (s, 2H), 7.35-7.42 (m, 3H), 7.48-7.53 (m, 1H),7.61 (s, 1H).

Example 95

N-[3-(2-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]-N'-(2,6-dichlorophenyl)urea(compound 95)

Yield 72.2%, m.p. 158°-159° C.

NMR (δ, ppm; CDCl₃) 2.10 (m, 2H), 2.90 (t, 2H), 2.99 (t, 2H), 6.65 (s,1H), 6.87 (s, 1H), 7.07 (t, 2H), 7.25-7.53 (m, 6H), 7.60 (s, 1H).

Example 96

N-[3-(2-Chlorophenyl)-5,6,7,8-tetrahydronaphthono[2,3-b]thiophen-2-yl]-N'-(2,6-diethylphenyl)urea(compound 96)

Yield 93.8%, m.p. 178°-180° C.

NMR (δ, ppm; DMSO-₆) 1.12 (t, 6H), 1.71 (m, 4H), 2.53 (q, 4H), 2.72 (t,2H), 2.82 (t, 2H), 6.68 (s, 1H), 7.06-7.25 (m, 3H), 7.45-7.60 (m, 4H),7.70-7.80 (m, 1H), 8.18 (s, 1H), 8.87 (s, 1H).

Example 97

N-[3-(2-Chlorophenyl)-5,6,7,8-tetrahydronaphtho[2,3-b]thiophen-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 97)

Yield 81.2%, m.p. 214°-216° C.

NMR (δ, ppm; DMSO-₆) 1.10 (d, 12H), 1.71 (m, 4H), 2.72 (t, 2H), 2.82 (t,2H), 3.07 (m, 2H), 6.68 (s, 1H), 7.12-7.33 (m, 3H), 7.46-7.60 (m, 4H),7.70-7.78 (m, 1H), 8.15 (s, 1H), 8.86 (s, 1H).

Example 98

N-[3-(2-Chlorophenyl)-5,6,7,8-tetrahydronaphtho[2,3-b]thiophen-2-yl]-N'-(2-isopropyl-6-methylphenyl)urea (compound 98)

Yield 95.8%, m.p. 138°-140° C.

NMR (δ, ppm; DMSO-₆) 1.13 (d, 6H), 1.71 (m, 4H), 2.17 (s, 2H) 2.71 (t,2H), 2.81 (t, 2H), 3.09 (m, 1H), 6.68 (s, 1H), 7.02-7.18 (m, 3H),7.45-7.60 (m, 4H), 7.70-7.78 (m, 1H), 8.20 (s, 1H), 8.88 (s, 1H).

Example 99

N-[3-(2-Chlorophenyl)-5,6,7,8-tetrahydronaphtho[2,3-b]thiophen-2-yl]-N'-(2,4-difluorophenyl)urea(compound 99)

Yield 71.6%, m.p. 134°-135° C.

NMR (δ, ppm; CDCl₃) 1.80 (m, 4H), 2.78 (t, 2H), 2.90 (t, 2H), 6.72-6.93(m, 3H), 7.12 (br, 2H), 7.33-7.58 (m, 5H), 7.88-8.01 (m, 1H).

Example 100

N-[3-(2,4-Dichlorophenyl)-5-nitro-1-benzothiophen-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 100)

Yield 48.9%, m.p. 145°-146° C.

NMR (δ, ppm; DMSO-₆) 1.10 (d, 12H), 3.07 (m, 2H), 7.17-7.35 (m, 3H),7.64-7.82 (m, 3H), 8.00-8.08 (m, 2H), 8.14-8.22 (m, 2H), 9.37 (s, 1H).

Example 101

N-[3-(2,4-Dichlorophenyl)-5-nitro-1-benzothiophen-2-yl]-N'-(2,4-difluorophenyl)urea(compound 101)

Yield 19.3%, m.p. 261°-263° C.

NMR (δ, ppm; DMSO-₆) 7.10 (t, 1H), 7.35 (t, 1H), 7.60-7.82 (m, 3H),7.98-8.25 (m, 4H), 9.10 (s, 1H), 9.60 (d, 1H).

Example 102

N-[3-(2-Chlorophenyl)-5,6-dimethoxy-1-benzothiophen-2-yl]-N'-(2,6-diethylphenyl)urea (compound 102)

To a stirred mixture of 500 mg of3-(2-chlorophenyl)-5,6-dimethoxy-1-benzothiophen-2-carboxylic acid and0.32 cc of diphenylphosphoryl azide in 5 cc of benzene was addeddropwise 0.15 cc of triethylamine at room temperature. The resultingmixture was stirred at room temperature for 15 minutes and then heatedunder reflux for 30 minutes. After cooling, 0.245 cc of2,6-diethylaniline was added, followed by refluxing for 2 hours. Aftercooling, water was added to the reaction mixture and extracted withethyl acetate. The extract was dried over magnesium sulfate, anddistilled to remove the solvent. The crude product thus obtained waspurified by a silica gel column chromatography (eluent: ethylacetate/hexane=3/7) to obtain 554 mg of compound 102.

Yield 78.3%, m.p. 229°-231° C.

NMR (δ, ppm; DMSO-₆) 1.11 (t, 6H), 2.53 (q, 4H), 3.63 (s, 3H), 3.80 (s,3H), 6.49 (s, 1H), 7.06-7.22 (m, 3H), 7.45 (s, 1H), 7.48 (m, 3H),7.70-7.78 (m, 1H), 8.14 (s, 1H), 8.80 (s, 1H).

The compounds described in Examples 103 to 119 were obtained in the samemanner as in Example 102.

Example 103

N-[3-(2-Chlorophenyl)-5,6-dimethoxy-1-benzothiophen-2-yl]-N'-(2,6-diisopropylphenyl)urea (compound 103)

Yield 96.3%, m.p. 135°-137° C.

NMR (δ, ppm; DMSO-₆) 1.10 (d, 12H), 3.09 (m, 2H), 3.64 (s, 3H), 3.82 (s,3H), 6.50 (s, 1H), 7.12-7.32 (m, 3H), 7.45 (s, 1H), 7.52-7.63 (m, 3H),7.73-7.80 (m, 1H), 8.12 (s, 1H), 8.80 (s, 1H).

Example 104

N-[3-(2-Chlorophenyl)-5,6-dimethoxy-1-benzothiophen-2-yl]-N'-(2-isopropyl-6-methylphenyl)urea(compound 104)

Yield 83.2%, m.p. 134°-137° C.

NMR (δ, ppm; DMSO-₆) 1.13 (d, 6H), 2.17 (s, 3H), 3.09 (m, 1H), 3.63 (s,3H), 3.80 (s, 3H), 6.49 (s, 1H), 7.03-7.18 (m, 3H), 7.45 (s, 1H),7.48-7.60 (m, 3H), 7.70-7.78 (m, 1H), 8.16 (s, 1H), 8.82 (s, 1H).

Example 105

N-[3-(2-Chlorophenyl)-5,6-dimethoxy-1-benzothiophen-2-yl]-N'-(2,4-difluorophenyl)urea (compound 105)

Yield 85.4%, m.p. 186°-187° C.

NMR (δ, ppm; DMSO-₆) 3.62 (s, 3H), 3.82 (s, 3H), 6.46 (s, 1H), 7.07 (dt,1H), 7.32 (dt, 1H), 7.45-7.62 (m, 4H), 7.70-7.78 (m, 1H), 8.08-8.20 (m,1H), 9.06 (s, 1H), 9.15 (d, 1H).

Example 106

N-[3-(2,4-Dichlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]-N'-(2,6-diisopropylphenyl)urea(compound 106)

Yield 41.4%, m.p. 220°-222° C.

NMR (δ, ppm; DMSO-₆) 1.10 (d, 12H), 2.02 (m, 2H), 2.83 (t, 2H), 2.91 (t,2H), 3.07 (m, 2H), 6.87 (s, 1H), 7.16 (d, 2H), 7.22-7.30 (m, 1H), 7.54(d, 1H), 7.60-7.68 (m, 2H), 7.92 (s, 1H), 8.04 (s, 1H), 8.90 (s, 1H).

Example 107

N-[3-(2,4-Dichlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]-N'-(2,4-difluorophenyl)urea(compound 107)

Yield 57.1%, m.p. 201°-202° C.

NMR (δ, ppm; DMSO-₆) 2.02 (m, 2H), 2.83 (t, 2H), 2.90 (t, 2H), 6.85 (s,1H), 7.07 (td, 1H), 7.33 (td, 1H), 7.45-7.73 (m, 3H), 7.91 (s, 1H),8.07-8.20 (m, 1H), 8.99 (s, 1H), 9.21 (s, 1H).

Example 108

N-(2,6-Diethylphenyl)-N'-[3-(2-fluorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]urea(compound 108)

Yield 78.4%, m.p. 223°-225° C.

NMR (δ, ppm; DMSO-₆) 1.11 (t, 6H), 2.02 (m, 2H), 2.51 (q, 4H), 2.84 (t,2H), 2.91 (t, 2H), 6.98 (s, 1H), 7.10-7.20 (m, 3H), 7.40-7.60 (m, 4H),7.64 (s, 1H), 8.20 (s, 1H), 8.97 (s, 1H).

Example 109

N-(2,6-Diethylphenyl)-N'-[3-(2-methylphenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]urea(compound 109)

Yield 70.3%, m.p. 188°-191° C.

NMR (δ, ppm; DMSO-d₆) 1.09 (t, 6H), 2.01 (m, 2H), 2.13 (s, 3H), 2.53 (q,4H), 2.82 (t, 2H), 2.91 (t, 2H), 6.80 (s, 1H), 7.05-7.55 (m, 7H), 7.64(s, 1H), 8.25 (s, 1H), 8.71 (s, 1H).

Example 110

N-(2,6-Diisopropylphenyl)-N'-[3-(2-methylphenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]urea(compound 110)

Yield 83.7%, m.p. 197°-199° C.

NMR (δ, ppm; DMSO-₆) 1.13 (d, 12H), 2.01 (m, 2H), 2.12 (s, 3H), 2.82 (t,2H), 2.91 (t, 2H), 3.08 (m, 2H), 6.80 (s, 1H), 7.11-7.52 (m, 7H), 8.19(s, 1H), 8.68 (s, 1H).

Example 111

N-(2-Isopropyl-6-methylphenyl)-N'-[3-(2methylphenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]urea(compound 111)

Yield 87.8%, m.p. 210°-213° C.

NMR (δ, ppm; DMSO-₆) 1.12 (d, 6H), 2.01 (m, 2H), 2.12 (s, 3H), 2.16 (s,3H), 2.81 (t, 2H), 2.91 (t, 2H), 3.03-3.15 (m, 1H), 6.79 (s, 1H),7.03-7.52 (m, 7H), 7.63 (s, 1H), 8.24 (s, 1H), 8.71 (s, 1H).

Example 112

N-(2,4-Difluorophenyl)-N'-[3-(2-methylphenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]-urea(compound 112)

Yield 89.0%, m.p. 185°-186° C.

NMR (δ, ppm; CDCl₃) 2.10 (m, 2H), 2.12 (s, 3H), 2.88 (t, 2H), 2.99 (t,2H), 6.71-6.86 (m, 2H), 6.98 (s, 1H), 7.03 (d, 1H), 7.15-7.35 (m, 5H),7.63 (s, 1H), 7.80-7.93 (s, 1H).

Example 113

N-(2,6-Diethylphenyl)-N'-[3-(2-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[f][1]-benzothiophen-2-yl]urea(compound 113)

Yield 81.5%, m.p. 202°-204° C.

NMR (δ, ppm; DMSO-₆) 1.08 (t, 6H), 2.00 (m, 2H), 2.50 (q, 4H), 2.79 (t,2H), 2.90 (t, 2H), 6.64 (s, 1H), 7.05-7.20 (m, 3H), 7.50 (d, 1H), 7.62(s, 1H), 7.77 (t, 1H), 7.88 (t, 1H), 8.00 (d, 1H), 8.06 (s, 1H), 8.71(s, 1H).

Example 114

N-(2,6-Diisopropylphenyl)-N'-[3-(2-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[f][1]-benzothiophen-2-yl]urea(compound 114)

Yield 74.7%, m.p. 217°-220° C.

NMR (δ, ppm; DMSO-₆) 1.10 (d, 12H), 2.00 (m, 2H), 2.79 (t, 2H), 2.91 (t,2H), 3.05 (m, 2H), 6.64 (s, 1H), 7.10-7.28 (m, 3H), 7.50 (d, 1H), 7.61(s, 1H), 7.77 (t, 1H), 7.89 (t, 1H), 7.95-8.05 (m, 2H), 8.68 (s, 1H).

Example 115

N-(2,4-Difluorophenyl)-N'-[3-(2-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]urea (compound 115)

Yield 79.2%, m.p. 132°-135° C.

NMR (δ, ppm; DMSO-₆) 2.00 (m, 2H), 2.79 (t, 2H), 2.91 (t, 2H), 6.64 (s,1H), 7.06 (td, 1H), 7.30 (td, 1H), 7.46 (d, 1H), 7.66 (s, 1H), 7.78 (t,1H), 7.87 (t, 1H), 8.01 (d, 1H), 8.08-8.18 (m, 1H), 8.98 (s, 1H), 9.06(s, 1H).

Example 116

N-(2,6-Diethylphenyl)-N'-[3-(2-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophen-2-yl]urea (compound 116)

Yield 89.0%, m.p. 205°-206° C.

NMR (δ, ppm; DMSO-₆) 1.11 (t, 6H), 2.01 (m, 2H), 2.53 (q, 4H), 2.81 (t,2H), 2.90 (t, 2H), 3.80 (s, 3H), 6.97 (s, 1H), 7.10-7.50 (m, 7H), 7.59(s, 1H), 8.33 (s, 1H), 8.60 (s, 1H).

Example 117

N-(2,6-Diethylphenyl)-N'-[3-(2-methylphenyl)-5,6,7,8-tetrahydronaphtho[2,3-b]thiophen-2-yl]urea (compound 117)

Yield 81.5%, m.p. 202°-204° C.

NMR (δ, ppm; DMSO-₆) 1.10 (t, 6H), 1.72 (m, 4H), 2.12 (s, 3H), 2.52 (q,4H), 2.69 (t, 2H), 2.81 (t, 2H), 6.66 (s, 1H), 7.05-7.53 (m, 8H), 8.24(s, 1H), 8.69 (s, 1s).

Example 118

N-(2,6-Diisopropylphenyl)-N'-[3-(2-methylphenyl)-5,6,7,8-tetrahydronaphtho[2,3-b]thiophen-2-yl]urea (compound 118)

Yield 74.7%, m.p. 217°-220° C.

NMR (δ, ppm ; DMSO-d₆) 1.10 (d, 12H), 1.72 (m, 4H), 2.12 (s, 3H), 2.69(t, 2H), 2.81 (t, 2H), 3.06 (m, 2H), 6.66 (s, 1H), 7.10-7.53 (m, 8H),8.20 (s, 1H), 8.68 (s, 1H).

Example 119

N-(2,4-Difluorophenyl )-N'-[3-(2-methylphenyl)5,6,7,8-tetrahydronaphtho[2,3-b]thiophen-2-yl]urea (compound 119)

Yield 79.3%, m.p. 132°-135° C.

NMR (δ, ppm; DMSO-₆) 1.72 (m, 4H), 2.07 (s, 3H), 2.69 (t, 2H), 2.82 (t,2H), 6.63 (s, 1H), 7.06 (td, 1H), 7.31-7.50 (m, 5H), 7.52 (s, 1H),8.08-8.20 (m, 1H), 9.07 (s, 1H), 9.15 (s, 1H).

Example 120

N-(2,4-Difluorophenyl)-N'-[3-phenyl-1-(p-toluenesulfonyl)-3-phenylindole-2-yl]urea(compound 120)

To a stirred mixture of 1.05 g of1-(p-toluenesulfonyl)-3-phenylindole-3-carboxylic acid and 0.60 cc ofdiphenylphosphoryl azide in 10 cc of benzene was added dropwise 0.39 ccof triethylamine at room temperature. The resulting mixture was stirredat room temperature for 15 minutes and then heated under reflux for 30minutes. After cooling, 0.285 cc of 2,4-difluoroaniline was added andthen stirred at room temperature for 30 minutes, followed by refluxingfor 2 hours. After cooling, water was added to the reaction mixture andextracted with ethyl acetate. The extract was dried over magnesiumsulfate, and distilled to remove the solvent. The crude product thusobtained was purified by a silica gel column chromatography (eluent:ethyl acetate/hexane=1/3) to obtain 780 mg of compound 120. Yield 55.8%,m.p. 244°-246° C.

NMR (δ, ppm; DMSO-₆) 2.28 (s, 3H), 6.94-7.08 (m, 1H), 7.22-7.57 (m,

11H), 7.77-7.91 (m, 3H), 8.08 (d, 1H), 8.72 (s, 2H).

The compounds described in Examples 121 to 125 were obtained in the samemanner as in Example 120.

Example 121

N-[3-(2-chlorophenyl)-5,7-dimethyl-1-(p-toluenesulfonyl)indole-2-yl]-N'-(2-isopropyl-6-methylphenyl)urea(compound 121)

Yield 62.1%.

NMR (δ, ppm; DMSO-d₆) 1.06 (d, 6H), 2.03 (s, 3H), 2.23 (s, 3H), 2.30 (s,3H), 2.60 (s, 3H), 3.08 (m, 1H), 6.55 (s, 1H), 6.90-7.60 (m, 12H), 7.83(s, 1H), 8.55 (s, 1H).

Example 122

N-[3-(2-Chlorophenyl)-5,7-dimethyl-1-(p-toluenesulfonyl)indole-2-yl]-N'-(2,4-difluorophenyl)urea(compound 122)

Yield 59.0%, m.p. 240°-241° C.

NMR (δ, ppm; CDCl₃) 2.27 (s, 3H), 2.35 (s, 3H), 2.76 (s, 3H), 6.71 (s,1H), 6.75-6.88 (m, 1H), 7.02-7.47 (m, 12H), 7.80-7.90 (m, 1H).

Example 123

N-[3-(2-Chlorophenyl)-5,7-dimethyl-1-methylindole-2-yl]-N'-(2-isopropyl-6-methylphenyl)urea(compound 123)

Yield 21.5%, m.p. 263°-264° C.

NMR (δ, ppm; DMSO-₆) 1.10 (d, 6H), 2.16 (s, 3H), 2.27 (s, 3H), 2.72 (s,3H), 3.10 (m, 1H), 3.90 (s, 3H), 6.72 (s, 1H), 6.82 (s, 1H), 7.02-7.18(m, 3H), 7.35-7.45 (m, 3H), 7.55-7.63 (m, 1H), 7.75 (broad, 1H), 8.30(s, 1H).

Example 124

N-[3-(2-Chlorophenyl)-5,7-dimethyl-1-methylindole-2-yl]-N'-(2,4-difluorophenyl)urea(compound 124)

Yield 59.0%, m.p. 240°-241° C.

NMR (δ, ppm; CDCl₃) 2.35 (s, 3H), 2.78 (s, 3H), 3.97 (s, 3H), 6.62 (s,2H), 6.72-6.82 (m, 2H), 6.88 (s, 1H), 7.06 (s, 1H), 7.26-7.35 (m, 2H),7.41-7.50 (m, 2H), 7.67-7.78 (m, 1H).

Example 125

N-[3-(2-Chlorophenyl)-5,7-dimethyl-1-methylindole-2-yl]-N'-(4-dimethylaminophenyl)urea(compound 125)

Yield 44.5%, m.p. 255°-256° C.

NMR (δ, ppm DMSO-d₆) 2.29 (s, 3H), 2.73 (s, 3H), 2.82 (s, 6H), 3.85 (s,3H), 6.66 (d, 2H), 6.73 (S, 1H), 7.20 (d, 2H), 7.31-7.42 (m, 3H), 7.57(d, 1H), 7.98 (s, 1H), 8.40 (s, 1H).

Reference Example 1

3-(2-Chlorophenyl)-5-fluorobenzofuran-2-carboxylic acid

1) 4-Fluorophenyl 2-chlorobenzoate (compound A)

To a stirred solution of 25 g of 4fluorophenol in 40 cc of pyridine and30 cc of toluene was added dropwise 40.9 g of 2-chlorobenzoylchloride atroom temperature. And the resulting mixture was stirred at roomtemperature for 16 hours. Ice water was added to the reaction mixtureand extracted with ethyl acetate. The ethylacetate layer was washed 4times with 1N HCl, dried over magnesium sulfate. The solvent wasdistilled off and the crude product thus obtained was recrystallizedfrom hexane to obtain 49.1 g of compound A. Yield: 87.8%.

2) 2-Chloro-5'-fluoro-2'-hydroxybenzophenone (compound B)

To a stirred solution of 2.5 g of compound A was added in small portions1.47 g of powdered aluminum chloride at 130° C. and stirring wascontinued for another 1 hour. After cooling 1N HCl and chloroform wasadded to the reaction mixture and the organic layer was separated. Theaqueous layer was extracted with chloroform. The combined organic layerwas dried over magnesium sulfate and distilled to remove the solvent.The crude product thus obtained was crystallized from hexane to obtain1.41 g of compound B. Yield: 56.3%.

3) Ethyl 6-(2-Chlorobenzoyl)-2,4-dimethylphenoxyacetate (compound C)

To a stirred mixture of 1.0 g of compound B and 1.1 g of potassiumcarbonate in 10 cc of dimethylformamide was added dropwise 0.53 cc ofethyl bromoacetate at room temperature. After the resulting mixture wasstirred at room temperature for 16 hours. The insoluble material wasfiltered off. To the filtrate was added water and ethylacetate and theaqueous layer was extracted with ethyl acetate. The combined organiclayer was washed three times with a saturated aqueous sodium chloridesolution and dried over magnesium sulfate. The solvent was distilled offand the crude product thus obtained was purified by a silica gel columnchromatography (eluent: ethyl acetate/hexane=1/4) to obtain 1.06 g ofcompound C. Yield: 78.7%.

4) Ethyl 3-(2-chlorophenyl)-5-fluorobenzofuran-2-carboxylate (compoundD)

To a stirred solution of sodium ethoxide prepared from 0.23 g of Na and10 cc of ethanol was added dropwise 3.4 g of compound C in 10 cc oftetrahydrofuran at room temperature. And the resulting mixture washeated under reflux for 30 minutes. After cooling, the reaction mixturewas poured into ice water and acidified with 1N HCl, which was thenextracted three times with chloroform. The combined organic layer waswashed with a saturated aqueous sodium chloride solution and dried overmagnesium sulfate. The solvent was distilled off and the crude productthus obtained was purified by a silica gel column chromatography(eluent: ethyl acetate/hexane=1/6) to obtain 0.89 g of compound D.Yield: 27.9%.

5) 3-(2-Chlorophenyl)-5-fluorobenzofuran-2-carboxylic acid

A mixture of 3.69 g of compound D and 1.95 g of powdered potassiumhydroxide in 30 cc of ethanol and 4 cc of water was heated under refluxfor 6 hours. After cooling, ice water was added and the resultingmixture was washed with hexane. The aqueous layer was acidified with 1NHCl, and extracted with chloroform, which was then dried over magnesiumsulfate. The solvent was distilled off to obtain 3.14 g of3-(2-chlorophenyl)-5-fluorobenzofuran-2-carboxylic acid. Yield: 93.3%.

The following compounds were obtained in the same manner as in ReferenceExample 1:

(1) 5-chloro-(2-chlorophenyl)benzofuran-2-carboxylic acid,

(2) 3-(2-chlorophenyl)-5-methylbenzofuran-2-carboxylic acid,

3) 3-(2-Chlorophenyl)-5-ethylbenzofuran-2-carboxylic acid,

(4) 3-(2-chlorophenyl)-5-n-hexylbenzofuran-2-carboxylic acid,

(5) 3-(2-chlorophenyl)-5-methoxybenzofuran-2-carboxylic acid,

(6) 3-(2-chlorophenyl)-5-dimethylaminomethylbenzofuran-2-carboxylicacid,

(7) 3-(2-chlorophenyl)-5-(1-pyrrolidinomethyl)benzofuran-2-carboxylicacid,

(8) 3-(2-chlorophenyl)-5-(1-morpholinomethyl)benzofuran-2-carboxylicacid,

(9)3-(2-chlorophenyl)-(4-methyl-1-piperazinomethyl)benzofuran-2-carboxylicacid,

(10) 3-(2-chlorophenyl)-5,6-dimethylbenzofuran-2-carboxylic acid,

(11) 3-(2-chlorophenyl)-5,7-dimethylbenzofuran-2-carboxylic acid,

(12)3-(2-chlorophenyl)-6,7-dihydro-5H-cyclopenta[f]benzofuran-2-carboxylicacid,

(13) 5-chloro-3-(2-fluorophenyl)benzofuran-2-carboxylic acid,

(14) 5-chloro-3-(2-methylphenyl)benzofuran-2-carboxylic acid,

(15) 5-chloro-3-(2-methylthiophenyl)benzofuran-2-carboxylic acid.

Reference Example 2

5-Methyl-3-phenylbenzofuran-2-carboxylic acid

1) Ethyl α-(4-Methylphenyl)benzoylacetate (compound E)

A mixture of 7.66 g of ethyl α-diazobenzoylacetate, 3.8 g of p-cresoland 150 mg of rhodium(II) acetate in 40 cc of carbon tetrachloride wasstirred at a temperature of 40-50° C. for 2 hours. After cooling, theinsoluble materials were filtered off and the solvent was distilled off.The crude product thus obtained was purified by a silica gel columnchromatography (eluent: chloroform/hexane=1/2) to obtain 2.59 g ofcompound E. Yield: 24.7%.

2) 5-Methyl-3-phenylbenzofuran-2-carboxylic acid

A mixture of 1.79 g compound E in 5 cc of concentrated sulfuric acid wasstirred under ice-cooling for 1 hour. The reaction mixture was pouredinto ice water and was extracted with chloroform, which was then washedwith water, a saturated aqueous sodium bicarbonate solution and asaturated aqueous sodium chloride solution successively, and dried overmagnesium sulfate. The solvent was distilled off and the residue wascrystallized from hexane to obtain 1.30 g of ethyl5-methyl-3-phenylbenzofuran-2-carboxylate (compound F). Yield: 77.3% orless. 3-Phenyl-5-methylbenzofuran-2-carboxylic acid was obtained in thesame manner as in the step 5 of Reference Example 1 except for usingcompound F.

Reference Example 3

5-Chloro-3-(2-chlorophenyl)-1-benzothiophene-2-carboxylic acid

1) 5-Chloro-2-methylthio-2'-chlorobenzophenone (compound G)

To 57.9 g of aluminum chloride was added dropwise 54.7 ml of2-chlorobenzoyl chloride at room temperature, and the resulting mixturewas stirred at room temperature for 30 minutes. Then, 24.0 g of4-chlorophenylmethyl sulfide was added dropwise at room temperature andstirring was continued for 16 hours. The reaction mixture was pouredinto ice water and extracted with ether, which was then washed withwater and an aqueous sodium bicarbonate solution. The extract was driedover magnesium sulfate and distilled to remove the solvent. The crudeproduct thus obtained was purified by a silica gel column chromatography(eluent: ethyl acetate/hexane=1/19) to obtain 13.1 g of5-chloro-2-methylthio-2'-chlorobenzophenone (compound G). Yield: 31.5%.

2) 5-Chloro-3-(2-chlorophenyl)-1-benzothiophen-2-carboxylic acid

A mixture of 4.9 g of compound G and 7.8 g of chloroacetic acid wasstirred at 120° C. for 10 hours. After cooling, water was added to thereaction mixture and the precipitate formed was collected by filtration.The precipitate was dissolved in ethyl acetate and washed with water.The solution was dried over magnesium sulfate and distilled to removethe solvent. The crude product thus obtained was washed with ether toobtain 4.45 g of5-chloro-3-(2-chlorophenyl)-1-benzothiophen-2-carboxylic acid. Yield:83.3%.

The following compounds were obtained in the same manner as in ReferenceExample 3:

(1) 3-(2-chlorophenyl)-5-methyl-1-benzothiophene--carboxylic acid,

(2) 3-(2-Chlorophenyl)-5-isopropyl-1-benzothiophene-2-carboxylic acid,

(3) 3-(2-chlorophenyl)-5,6-dimethyl-1-benzothiophene-2-carboxylic acid,

(4)3-(2-chlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophene-2-carboxylicacid,

(5)3-(2-chlorophenyl)-5,6,7,8-tetrahydronaphtho[2,3-b]thiophene-2-carboxylicacid,

(6) 3-(2,4-dichlorophenyl)-5-nitro-1-benzothiophene-2-carboxylic acid,

(7) 3-(2-chlorophenyl)-5,6-dimethoxy-1-benzothiophene-2-carboxylic acid,

(8)3-(2,4-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophene-2-carboxylicacid,

(9)3-(2-methylphenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophene-2-carboxylicacid,

(10)3-(2-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[f][1]benzothiophene-2-carboxylicacid,

(11)3-(2-methylphenyl)-5,6,7,8-tetrahydronaphtho[2,3-b]thiophene-2-carboxylicacid.

Reference Example 4

3-Phenyl-1-(p-toluenesulfonylindole)-2-carboxylic acid

2-(p-Toluenesulfonylamino)benzophenone (compound H)

To a stirred solution of 15.0 g of 2-aminobenzophenone in 7.5 cc ofpyridine was added 14.5 g of p-toluenesulfonyl chloride underice-cooling. And the resulting mixture was stirred at room temperaturefor 16 hours. 2N HCl was added to the reaction mixture and extractedwith ethyl acetate. The extract was washed with water and dried overmagnesium sulfate. The solvent was distilled off and the crude crystalsthus obtained were recrystallized from isopropanol to obtain 22.0 g ofcompound H. Yield: 82.4%.

t-Butyl N-(2-benzoylphenyl)-N-(p-toluenesulfonyl)aminoacetate (compoundI)

To a stirred solution of 5.0 g of compound H in 10 cc ofdimethylformamide was added 0.56 g of 63% sodium hydride in 5 cc ofdimethylformamide under ice-cooling and the mixture was stirred for 30minutes. Then, 2.3 cc of t-butyl bromoacetate was added dropwise at thesame temperature and stirring was continued for 16 hours. Water wasadded to the reaction mixture and the desired compound was extractedwith ethyl acetate. The extract was washed with water and dried overmagnesium sulfate. The solvent was distilled off and the crude productthus obtained was washed with hexane to obtain 6.31 g of compound I.Yield: 95.4%.

3) t-Butyl 3-phenyl-1-(p-toluenesulfonyl)indole-2-carboxylate (compoundJ)

To a stirred solution of 2.30 g of compound I in 175 cc of methanol wasadded 0.39 g of sodium methoxide at room temperature and the mixture wasstirred for 16 hours. The methanol was distilled off and to the residuewas added water, followed by extraction with ethyl acetate. The extractwas dried over magnesium sulfate and distilled to remove the solvent.The resulting crude product was dissolved in 50 cc of benzene, followedby adding dropwise thereto 1.41 cc of pyridine and then 0.52 g ofthionyl chloride at room temperature, and the resulting mixture wasstirred at room temperature for 1 hour. Water was added to the reactionmixture and extracted with ethyl acetate. The extract was dried overmagnesium sulfate and distilled to remove the solvent the crude productthus obtained was purified by a silica gel column chromatography(eluent: ethyl acetate/hexane=1/4) to obtain 2.55 g of compound J.Yield: 80.2%.

3-Phenyl-1-(p-toluenesulfonyl)indole-2-carboxylic acid

To a stirred solution of 2.55 g of compound J in 10 cc of methylenechloride was added 2.20 g of trichloroacetic acid under ice-cooling andthe mixture was stirred for 16 hours. Water was added to the reactionmixture, the desired compound was extracted with ethyl acetate. Theextract was dried over magnesium sulfate and distilled to remove thesolvent. The crude product thus obtained was purified by a silica gelcolumn chromatography (eluent: ethyl acetate/hexane=3/7) to obtain 2.10g of 3-phenyl-1-(p-toluenesulfonyl)indole-2-carboxylic acid. Yield:94.1%.

5,7-Dimethyl-3-phenyl-1-(p-toluenesulfonyl)indole-2-carboxylic acid wasobtained in the same manner as in Reference Example 4.

Reference Example 5

3-(2-Chlorophenyl)-1,5,7-trimethylindole-2-carboxylic acid

Methyl1-(2-chlorobenzoyl)-3-(2-chlorophenyl)-5,7-dimethylindole-2-carboxylate(compound K) was obtained in the same manner as for compounds I and J inReference Example 4. In 20 cc of methanol was dissolved 0.96 g ofcompound K, followed by adding thereto 4.2 cc of 2N sodium hydroxide,and the resulting mixture was heated under reflux for 2 hours. Aftercooling, the mixture was acidified with 2N HCl, followed by extractionwith ethyl acetate. The extract was dried over magnesium sulfate anddistilled to remove the solvent. The resulting crude product wasdissolved in 2 cc of dimethylformamide, and 0.26 g of 63% sodium hydridein 1.5 cc of dimethylformamide was added at room temperature. Theresulting mixture was stirred at room temperature for 30 minutes, andthen 0.4 cc of methyl iodide was added dropwise and stirred for 2 hours.Water was added to the reaction mixture, followed by extraction withethyl acetate. The extract was dried over magnesium sulfate anddistilled to remove the solvent. The crude product thus obtained waswashed with hexane to obtain 0.41 g of methyl3-(2-chlorophenyl)-1,5,7-trimethylindole-2-carboxylate (compound L).

3-(2-Chlorophenyl)-1,5,7-trimethylindole-2-carboxylic acid was obtainedin the same manner as in Reference Example 1 except for using compoundL.

The compounds of the present invention are administered as a propylacticand therapeutic agent for hypercholesterolemia and atherosclerosisorally or parenterally (intramuscularly, subcutaneously orintravenously). They are administered to human beings preferably orally.Since the compounds of the present invention are applicable inthemselves as ACAT inhibitors, they are contained in compositions asactive ingredients usually in an amount of 0.01 to 100% by weight.Although the dose of the compounds is varied depending on the conditionof a disease, age, sex, body weight, administration route, etc., thedose for an adult is usually 0.1 to 1000 mg per day.

When the compound of the present invention is formulated into apharmaceutical form, it is prepared into powder, granules, tablets,dragees, capsules, pills, a suspension, solution, emulsion, ampule,injection, isotonic solution or the like by a conventional preparationmethod. When an oral solid pharmaceutical is prepared, an excipient andoptionally a binder, wetting agent, disintegrator, surfactant,lubricant, dispersant, taste-improver, odor-improver, etc. are added tothe active ingredient, and the resulting mixture is made into tablets,coated tablets, granules, capsules or the like by a conventional method.The excipient includes, for example, lactose, glucose, sorbitol, cornstarch and mannitol. The binder includes, for example, poly(vinylalcohol)s, poly(vinyl ether)s, ethyl cellulose, gum arabic, gelatin,hydroxypropyl cellulose and poly(vinylpyrrolidone)s. The disintegratorincludes, for example, calcium carbonate, calcium citrate, dextrin,starch and gelatin powder. The lubricant includes, for example,magnesium stearate, talc and poly(ethylene glycol)s. The odor-improverincludes, for example, cocoa powder, menthol, and peppermint oil. Thetablets and the granules may be properly coated with a frosting, gelatinor the like if necessary. When an injection is prepared, a pH adjustor,buffer, surfactant, solubilizer, solvent, stabilizer, preservative, etc.are added to the active ingredient if necessary, and the resultingmixture is made into a subcutaneous, intramuscular or intravenousinjection by a conventional method.

Formulation examples are described below but they are not intended inany way to limit the scope of the invention. In the formulationexamples, parts are all by weight.

Formulation Example 1

A powder was prepared by mixing uniformly and pulverizing or granulatingfinely the following ingredients:

    ______________________________________                                        Each compound of the invention                                                                    10 parts                                                  Magnesium stearate  10 parts                                                  Lactose             80 parts                                                  ______________________________________                                    

Formulation Example 2

Granules were prepared by kneading together uniformly, grinding, andgranulating the following ingredients, followed by sieving:

    ______________________________________                                        Each compound of the invention                                                                    50 parts                                                  Starch              10 parts                                                  Lactose             15 parts                                                  Ethyl cellulose     20 parts                                                  Poly(vinyl alcohol)  5 parts                                                  Water               30 parts                                                  ______________________________________                                    

Formulation Example 3

Tablets with a diameter of 10 mm were prepared by mixing 99 parts of thegranules obtained in Formulation Example 2 with 1 part of calciumstearate, and compression-molding the resulting mixture.

Formulation Example 4

Granules were prepared in the same manner as in Formulation Example 2except for using the following ingredients:

    ______________________________________                                        Each compound of the invention                                                                    95 parts                                                  Poly(vinyl alcohol)  5 parts                                                  Water               30 parts                                                  ______________________________________                                    

To 90 parts of the granules obtained was added 10 parts of crystallinecellulose, and the resulting mixture was compression-molded into tabletswith a diameter of 8 mm. Then, the tablets were made into dragee by theuse of suitable amounts of a mixed suspension of syrup, gelatin andprecipitated calcium carbonate and a coloring agent.

Formulation Example 5

An injection was prepared by mixing by heating, and then sterilizing thefollowing ingredients:

    ______________________________________                                        Each compound of the invention                                                                    0.5       part                                            Nonionic surfactant 2.5       parts                                           Physiological saline                                                                              97        parts                                           ______________________________________                                    

Formulation Example 6

Capsules were prepared by packing the powder obtained in FormulationExample 1 into commercially available capsular containers.

Next, test examples are described below for proving the effectiveness ofthe present invention.

Test Example 1

Inhibitory activity on acyl-CoA:cholesterol Oacyltransferase (ACAT)

The enzyme used in the test was prepared according to the method ofHeider et al. [J. Lipid, Res. 24, 1127 (1983)]. The intestinal mucosa ofa white rabbit was homogenized and microsomal fraction was obtained bystepwise centrifugation. The microsomal fraction was suspended in 0,154Mphosphate buffer (pH 0 7.4) and stored at -80° C. until use.

ACAT activity was determined by a modification of the method of Helgerudet al. [J. Lipid Res. 22, 271 (1981)] by measuring radioactivityincorporated into cholesterol esters from [1-14C]oleyl-CoA, as anindication. As to the ACAT-inhibiting activity of each compound to betested, the inhibition rate was calculated by the following equation.The results obtained are shown in Table 2.

    ______________________________________                                        Inhibition rate (%) =                                                          ##STR18##                                                                    Compound        (Inhibition rate %)                                           No.             1      0.01 μM                                             ______________________________________                                        1                      49.8                                                   2                      58.3                                                   4               77.9                                                          5               98.5   15.4                                                   7               99.1   37.2                                                   8               97.4   24.9                                                   12              99.4   82.9                                                   13              99.4   84.9                                                   15              99.4   76.8                                                   19                     71.3                                                   22                     69.3                                                   25                     73.3                                                   26                     41.2                                                   27                     63.5                                                   30                     58.4                                                   36              98.9   37.6                                                   37              99.5   74.7                                                   38              99.5   77.2                                                   39              99.4   70.9                                                   43              99.5   52.1                                                   45              94.0                                                          46              92.7                                                          47              93.0                                                          48              95.6   6.8                                                    49              99.1   51.9                                                   53                     43.7                                                   55                     32.1                                                   58                     69.2                                                   60                     82.6                                                   61                     65.6                                                   62                     91.6                                                   63                     72.1                                                   65              99.1   56.5                                                   72                     60.6                                                   76                     71.0                                                   77                     51.7                                                   80                     69.9                                                   81                     41.4                                                   82                     67.0                                                   83                     81.3                                                   84                     78.6                                                   87                     60.4                                                   88                     85.8                                                   89                     44.4                                                   90                     75.4                                                   91                     65.0                                                   92                     81.7                                                   93                     69.7                                                   94                     76.7                                                   95                     66.4                                                   96                     80.7                                                   98                     66.0                                                   99                     90.1                                                   100                    18.4                                                   102                    43.3                                                   107                    36.2                                                   109                    80.1                                                   111                    69.2                                                   113                    43.5                                                   119                    79.5                                                   120             60.4                                                          121             85.8                                                          122             75.4                                                          124             81.7                                                          ______________________________________                                    

Test Example 2

Serum cholesterol lowering activity in hamsters fed on ahigh-cholesterol diet

Male Syrian hamsters of 10-week-old were divided into three groups. Thefirst group (normal group) was fed an ordinary diet for 4 days. Thesecond group (control group) was fed a high cholesterol diet (containing0.5% cholesterol and 8.0% coconut oil for 4 days. The third group(treated group) was fed a high cholesterol diet and was treated with acompound for 4 days. Simultaneously with the beginning of the abovefeeding, the compound suspended in a 0.5% carboxymethyl cellulosesolution was administered to the treated group, in a dose of 30 mg (interms of the compound) per kg of body weight per day for 4 days. A 0.5%carboxymethyl cellulose solution was also administered to the normalgroup and the control group in the same manner as above. After 24 hoursof the last administration, blood was collected and the cholesterolconcentration in serum was measured by an enzymatic method. Thereduction rate of the total serum cholesterol concentration wascalculated from values obtained for the three groups by the followingequation. The results obtained are shown in Table 3. ##EQU1## wherein A:the serum cholesterol concentration of the control group.

B: the serum cholesterol concentration of the compound treated group.

C: the serum cholesterol concentration of the normal group.

                  TABLE 3                                                         ______________________________________                                               Compound                                                                              Reduction                                                             No.     rate (%)                                                       ______________________________________                                               12      55.0                                                                  37      59.3                                                                  80      85.9                                                                  109     71.5                                                           ______________________________________                                    

Test Example 3

Inhibitory effect on cholesterol esterification in macrophages

The test was carried out by a modification of the method of Goldstein etal. [Pro. Nat. Acad. Sci. USA 71, 4288 (1974)]. J774 A.1 cells, themouse macropharge-like cell line, were suspended in Dulbecco's modifiedEagle's medium (DMEM) containing 10% fetal calf serum (FCS), in aproportion of 3×10⁵ cells per 2 ml and were seeded into in 6-wellplates. The cells were cultured under a humidified atmosphere of 95%air/5% CO₂ at 37° C. for 24 hours. The medium was replaced by 1 ml ofDMEM containing 10% of FCS and 50 μg/ml of acetylated human low densitylipoprotein (AcLDL), followed by culturing for 16 hours. Fivemicroliters each compound was dissolved in dimethyl sulfoxide andsolution was added to the medium, followed by culturing for another 2hours. Then, [14C]oleate (2×10⁶ dpm/well) bovine serum albumin complexwas added in the medium. After 2 hours of culture cells were collectedand the cholesterol-esterifying activity was determined by measuringradioactivity incorporated into cholesterol esters in the cells. Therecovery of the cholesterol esters was determined by the addition of[3H]cholesteryl oleate, and the esterifying activity was corrected usingthe recovery. As to the inhibitory activity on cholesterolesterification of the compound to be tested, the inhibition rate wascalculated by the following equation. The results obtained are shown inTable 4. ##EQU2## wherein A: the cholesterol-esterifying activity ofAcLDL-loaded cells to which the compound to be tested was-added.

B: the cholesterol-esterifying activity of AcLDL-loaded cells to whichdimethyl sulfoxide was added.

                  TABLE 4                                                         ______________________________________                                                         Inhibition                                                   Compound         rate (%)                                                     No.              1      0.1 μM                                             ______________________________________                                        12               99.5   93.0                                                  80               96.9   85.3                                                  ______________________________________                                    

Effect of the Invention

The N-heteroaryl-N'-phenylurea derivatives of the present invention haveACAT-inhibitory activity and are useful as a prophylactic andtherapeutic agent for hypercholesterolemia, atherosclerosis and variousdiseases caused by them.

What is claimed is: .[.1. An N-heteroaryl-N'-phenylurea derivativerepresented by the general formula (I): ##STR19## wherein R¹ and R²,which may be the same or different, are hydrogen atoms; halogen atoms;unsubstituted C₁ -C₁₀ alkyl groups; substituted C₁ -C₆ alkyl groupshaving a C₂ -C₈ -dialkylamino group as the substituent; substituted C₁-C₆ alkyl groups having as the substituent a saturated cyclic aminogroup which may have a heteroatom in the ring; C₁ -C₆ alkoxy groups; ornitro groups, R¹ and R² being able to be taken together to represent aC₃ -C₆ alkylene group, R³ and R⁴, which may be the same or different,are hydrogen atoms, halogen atoms, C₁ -C₆ alkyl groups, C₁ -C₆ haloalkylgroups, C₁ -C₆ alkoxy groups or C₁ -C₆ alkylthio groups, R⁵, R⁶ and R⁷,which may be the same or different, are hydrogen atoms, halogen atoms,C₁ -C₈ alkyl groups, C₁ -C₆ haloalkyl groups, C₃ -C₇ alkenyl groups, C₁-C₆ alkoxy groups, C₁ -C₆ alkylthio groups or C₂ -C₈ -dialkylaminogroups, and X is --S-- or a pharmacologically acceptable saltthereof..]..[.2. An N-heteroaryl-N'-phenylurea derivatives according toclaim 1, wherein R¹ is a halogen atom or a C₁ -C₁₀ alkyl group, R² is ahydrogen atom or a C₁ -C₆ alkyl group, R¹ and R² being able to be takentogether to represent a C₃ -C₆ alkylene group, R³ is a halogen atom, aC₁ -C₄ alkyl group, a C₁ -C₄ alkylthio group or trifluoromethyl group,R⁴ is a hydrogen atom or a halogen atom, R⁵ and R⁶ which may be the sameor different, are halogen atoms or C₁ -C₄ alkyl groups, and R7 is ahydrogen atom or a halogen atom..]..[.3. An N-heteroaryl-N'-phenylureaderivative according to claim 1, wherein R¹ is a chlorine atom or a C₁-C₈ alkyl group, R² is a halogen atom or a C₁ -C³ alkyl group, R¹ and R²being able to be taken together to represent a C₃ -C₄ alkylene group, R³is a halogen atom, a C₁ -C₄ alkyl group or a C₁ -C₄ alkylthio group, R⁴is a hydrogen atom, R⁵ and R⁶ which may be the same, are halogen atomsor C₁ -C₄ alkyl groups, and R⁷ is a hydrogen atom..]..[.4. Apharmaceutical composition for inhibiting acyl-CoA:cholesterolO-acryltransferase comprising as active ingredient a compoundrepresented by the general formula (I): ##STR20## wherein R¹ and R²,which may be the same or different, are hydrogen atoms; halogen atoms;unsubstituted C₁ -C₁₀ alkyl groups; substituted C₁ -C₆ alkyl groupshaving a C₂ -C₈ -dialkylamino group as the substituent; substituted C₁-C₆ alkyl groups having as the substituent a saturated cyclic aminogroup which may have a heteroatom in the ring; C₁ -C₆ alkoxy groups; ornitro groups, R¹ and R² being able to be taken together to represent aC₃ -C₆ alkylene group, R³ and R⁴, which may be the same or different,are hydrogen atoms, halogen atoms, C₁ -C₆ alkyl groups, C₁ -C₆ haloalkylgroups, C₁ -C₆ alkoxy groups or C₁ -C₆ alkylthio groups, R⁵, R⁶ and R⁷,which may be the same or different, are hydrogen atoms, halogen atoms,C₁ -C₈ alkyl groups, C₁ -C₆ haloalkyl groups, C₃ -C₇ alkenyl groups, C₁-C₆ alkoxy groups, C₁ -C₆ alkylthio groups or C₂ -C₈ -dialkylaminogroups, and X is --S-- or a pharmacologically acceptable salt thereof,and a pharmacologically acceptable carrier..]..[.5. A pharmaceuticalcomposition for inhibiting acyl-CoA:chlesterol O-acyltransferaseaccording to claim 4, wherein R¹ is a halogen atom or a C₁ -C₁₀ alkylgroup, R² is a hydrogen atom or a C₁ -C₆ alkyl group, R¹ and R² beingable to be taken together to represent a C₃ -C₆ alkylene group, Rhu is ahalogen atom, a C₁ -C₄ alkyl group, a C₁ -C₄ alkylthio group ortrifluoromethyl group, R⁴ is a hydrogen atom or a halogen atom, R⁵ andR⁶ which may be the same or different, are halogen atoms or C₁ -C₄ alkylgroups, and R⁷ is a hydrogen atom or a halogen atom..]..[.6. Apharmaceutical composition for inhibiting acyl-CoA:cholesterolO-acyltransferase according to claim 4, wherein R¹ is a chlorine atom ora C₁ -C₈ alkyl group, R² is a hydrogen atom or a C₁ -C₃ alkyl group, R¹and R² being able to be taken together to represent a C₃ -C₄ alkylenegroup, R³ is a halogen atom, a C₁ -C₄ alkyl group or a C₁ -C₄ alkylthiogroup, R⁴ is a hydrogen atom, R⁵ and R⁶ which may be the same, arehalogen atoms or C₁ -C₄ alkyl groups, and R⁷ is a hydrogenatom..]..Iadd.7. A compound consisting ofN-(2,6-Diethylphenyl)-N'-(3-(2-methylphenyl)-6,7-dihydro-5H-cyclopenta(f)(1)benzothiophen-2-yl-urea..Iaddend..Iadd.8. A pharmaceutical composition for inhibitingacyl-CoA:cholesterol O-acryltransferase comprising as active ingredient,a compound, N-heteroaryl-N'-phenylurea derivative consisting ofN-(2,6-Diethylphenyl)-N'-(3-(2-methylphenyl)-6,7-dihydro-5H-cyclopenta(f)(1)benzothiophen-2-yl)urea,or a pharmacologically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. .Iaddend.